The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models

Altered plasmalogen metabolism may also contribute to the tissue-specific manifestations of RDLKD.

“In addition, altered plasmalogen metabolism may also contribute to the tissue-specific manifestations of RDLKD.”

• cites Herzog et al., 2018 sourcePartly supported

  The Discussion reports decreased ether phospholipids, including plasmalogens, in fibroblasts from several peroxisomal disorders. It does not address RDLKD or whether altered plasmalogen metabolism contributes to its tissue-specific manifestations. (LLM, conf=0.84)

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• cites Yagita et al., 2017 sourceDisputed

  The Results passage on PlsEtn reports unchanged levels in ACBD5-deficient fibroblasts and concludes that ACBD5 deficiency has no apparent impact on its biosynthesis. The Discussion instead proposes accumulation of very-long-chain fatty acids as a contributor to the retinal phenotype. These fibroblast findings do not rule out every tissue-specific possibility, but the paper does not propose altered plasmalogen metabolism as a contributor. (LLM, conf=0.82)

  Checked by a reasoning model — may be wrong.

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Four RDLKD patients were significantly underweight.

“while four patients were significantly underweight (Al Shamsi et al., 2025).”

• cites Al Shamsi et al., 2025 sourceDisputed

  The case descriptions and anthropometry table report markedly low weights for cases one and three, but case two’s weight was at the 8th percentile and case four’s at the 5th–10th percentile. The Discussion states that cases four and five had no growth abnormality. These findings contradict the claim that four patients were significantly underweight. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

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Data from patient fibroblasts do not indicate a significant reduction of DHA in phospholipids.

“Data from patient fibroblasts do not indicate a significant reduction of DHA in phospholipids (Herzog et al., 2018; Yagita et al., 2017).”

• cites Herzog et al., 2018 sourceDisputed

  The Results section, “Decrease of phospholipid species containing docosahexaenoic acid” (page unavailable), reports decreased DHA-containing phospholipid species in ACOX1- and DBP-deficient patient fibroblasts compared with controls. It says this decrease was not observed in ALD cells. Although the passage does not state a statistical significance test for DHA specifically, it contradicts the claim’s broad assertion that patient-fibroblast data do not indicate a reduction. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

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• cites Yagita et al., 2017 sourceSupported

Acbd2-/- mice did not develop symptoms.

“Interestingly, Acbd1–/– mice, despite high VLCFA accumulation, do not develop cerebral disease and instead model the milder peripheral adrenomyelopathy, with late-onset symptoms appearing around 20 months of age, whereas Acbd2–/– mice did not develop symptoms (Pujol et al., 2004).”

• cites Pujol et al., 2004 sourceDisputed

  The paper reports no overt pathology or behavioural abnormalities in ALDR (ABCD2)-deficient mice through at least six months, but that does not support an unqualified claim that they never developed symptoms. The Spinal cord histopathology section reports axonal pathology at 12 months and pathology similar to that of ALD-deficient mice at 22 months; page numbers are unavailable in our copy. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

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Cerebral atrophy with dilatation of the sulci and ventricles on MRI scans was observed in only two ACBD5-deficient patients.

“However, cerebral atrophy—with dilatation of the sulci and ventricles on MRI scans—was observed in only two patients (Bartlett et al., 2021; Rudaks et al., 2024; Supplementary Table 1), indicating that widespread grey matter degeneration is potentially relatively rare.”

• cites Bartlett et al., 2021 sourceNot checked — no full text of the source
• cites Rudaks et al., 2024 sourcePartly supported

  The case description (section 1, page unavailable) reports progressive cerebral atrophy and dilation of the lateral and third ventricles in one patient. It does not report sulcal dilation or establish that only two ACBD5-deficient patients had this combination of MRI findings. (LLM, conf=0.86)

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Affective instability was reported in one ACBD5-deficient patient.

“Additionally, affective instability was reported in one patient (Rudaks et al., 2024), suggesting a possible neuropsychiatric component to RDLKD—a feature that remains largely unexplored in peroxisomal disorders.”

• cites Rudaks et al., 2024 sourceSupported

To date, eight publications have reported on 16 patients with ACBD5 deficiency.

“To date, eight publications have reported on 16 patients with ACBD5 deficiency”

• cites Abu-Safieh et al., 2013 sourcePartly supported

  The Results section (‘Exome as a discovery tool for novel RD genes’; page unavailable) describes three affected siblings with an ACBD5 splice-site variant and near-absence of ACBD5 protein. It does not report a tally of eight publications or 16 patients, so it supports an ACBD5 patient report but not the attributed totals. (LLM, conf=0.83)

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• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Bartlett et al., 2021 sourceNot checked — no full text of the source

One ACBD5-deficient patient showed no cognitive impairment despite prolonged disease progression.

“Interestingly, while one patient showed no cognitive impairment despite prolonged disease progression (Al Shamsi et al., 2025), febrile convulsions were reported in two others already during early childhood (Gorukmez et al., 2022), highlighting the broad phenotypic variability/severity of the disorder.”

• cites Al Shamsi et al., 2025 sourceSupported

Cognitive symptoms in RDLKD range from mild learning difficulties to severe deficits in speech and comprehension.

“The cognitive symptoms ranged from mild learning difficulties (Al Shamsi et al., 2025) to severe deficits in speech and comprehension (Bartlett et al., 2021).”

• cites Al Shamsi et al., 2025 sourceSupported
• cites Bartlett et al., 2021 sourceNot checked — no full text of the source

MRI signal changes were detected in motor function-related gray matter structures, including the basal ganglia (three patients) and the red nucleus (two patients), in ACBD5 deficiency.

“Notably, in addition to white matter abnormalities in the CNS, MRI signal changes were also detected in motor function-related gray matter structures, including the basal ganglia (three patients; Rudaks et al., 2024; Al Shamsi et al., 2025) and the red nucleus (two patients; Al Shamsi et al., 2025).”

• cites Rudaks et al., 2024 sourcePartly supported

  The Investigations passage (indexed under Conclusion; page unavailable) reports increased T2 signal in cerebral white matter, including tracts of the basal ganglia, in one patient. It does not report signal changes in basal ganglia gray matter or findings in three patients. The red-nucleus finding is cited only to Al Shamsi et al., not to Rudaks et al. (LLM, conf=0.86)

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• cites Al Shamsi et al., 2025 sourcePartly supported

  The Figure 1 caption (under Case three; page unavailable) identifies the red nuclei in MRI images of two patients, but describes their striking appearance as a consequence of surrounding white-matter changes, not as signal changes in the red nuclei themselves. The case MRI summary (under Case two; page unavailable) reports white-matter abnormalities and does not document basal-ganglia signal changes in three patients. (LLM, conf=0.84)

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Cognitive impairments were reported in six ACBD5-deficient patients.

“Beyond motor and sensory deficits, cognitive impairments were reported in six patients (Ferdinandusse et al., 2017; Bartlett et al., 2021; Rudaks et al., 2024; Al Shamsi et al., 2025), and delayed language development in five (Ferdinandusse et al., 2017; Bartlett et al., 2021; Gorukmez et al., 2022; Hasturk et al., 2024; Al Shamsi et al., 2025; Supplementary Table 1).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Bartlett et al., 2021 sourceNot checked — no full text of the source
• cites Rudaks et al., 2024 sourceSupported

Rod-cone or cone-rod dystrophies affecting both photoreceptor types were described in at least nine patients.

“Rod-cone or cone-rod dystrophies, affecting both photoreceptor types, were described in at least nine patients”

• cites Abu-Safieh et al., 2013 sourcePartly supported

  The introductory passage explains that rod-cone and cone-rod dystrophies eventually affect both photoreceptor types. The Results (Clinical characteristics) and Methods (Human subjects) show that the study included patients with cone-rod dystrophy, but the passages found do not establish the claimed minimum of nine patients. (LLM, conf=0.80)

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• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Bartlett et al., 2021 sourceNot checked — no full text of the source

ACBD5 is specifically required for β-oxidation of VLCFA.

“reinforcing the notion that ACBD5 is specifically required for β-oxidation of VLCFA”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Yagita et al., 2017 sourcePartly supported

  The Results section reports that ACBD5-deficient fibroblasts have reduced VLCFA β-oxidation while the measured PlsEtn and DHA pathways appear unaffected, supporting a relatively specific role. But C24:0 β-oxidation retained about 65% of control activity, so the paper supports ACBD5 being required for efficient VLCFA β-oxidation, not absolutely required for it (Results, Fig. 4E–G; page unavailable). (LLM, conf=0.86)

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In X-ALD, white matter lesions typically extend from parieto-occipital to frontal regions.

“In X-ALD, white matter lesions typically extend from parieto-occipital to frontal regions (Thakkar et al., 2024), while in RDLKD, current MRI data do not suggest a consistent regional pattern.”

• cites Thakkar et al., 2024 sourceSupported

No abnormalities in phytanic acid α-oxidation were detected in ACBD5-deficient patient fibroblasts.

“No abnormalities in phytanic acid α-oxidation were detected, reinforcing the notion that ACBD5 is specifically required for β-oxidation of VLCFA (Ferdinandusse et al., 2017; Yagita et al., 2017).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Yagita et al., 2017 sourcePartly supported

  The Discussion (page unavailable) reports normal phytanic acid levels in the plasma of one ACBD5-deficient patient, supporting the narrower observation that no plasma abnormality was detected. It does not report a phytanic acid α-oxidation measurement in patient fibroblasts and explicitly leaves open whether ACBD5 deficiency affects cellular branched-chain fatty acid homeostasis. (LLM, conf=0.88)

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RNAi-mediated knockdown of ACBD5 in HeLa cells reduced peroxisomal autophagy rates.

“While RNAi-mediated knockdown of ACBD5 in HeLa cells reduced peroxisomal autophagy rates (Nazarko et al., 2014), knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy (Ferdinandusse et al., 2017; Kors et al., 2024).”

• cites Nazarko et al., 2014 sourceSupported

The presence of other PO-ER tether proteins such as ACBD4 may partially compensate in peroxisome biogenesis in ACBD5 deficiency.

“The presence of other PO-ER tether proteins such as ACBD4 may partially compensate in peroxisome biogenesis (Costello et al., 2023).”

• cites Costello et al., 2023 sourcePartly supported

  The Results (page unavailable) show that overexpressed ACBD4 restored peroxisome–ER contacts in ACBD5-knockout cells, and the Discussion says ACBD4 can compensate for loss of ACBD5 in tethering. The paper links these contacts to peroxisome biogenesis, but does not show that ACBD4 compensates for biogenesis itself. (LLM, conf=0.82)

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Despite a role for ACBD5 in PO-ER contact site formation and phospholipid transfer for membrane expansion, total peroxisomal number is not affected in ACBD5-deficient cells.

“Notably, despite a role for ACBD5 in PO-ER contact site formation and phospholipid transfer for membrane expansion, total peroxisomal number is not affected (Yagita et al., 2017).”

• cites Yagita et al., 2017 sourcePartly supported

  In the peroxisome-biogenesis results (page unavailable), ACBD5-deficient fibroblasts retained peroxisomal structures and normal protein import. The Discussion (page unavailable) says a marked accumulation of peroxisomes in ACBD5-knockout HeLa cells is unlikely, but does not establish that total peroxisomal number is unchanged. The cited paper also does not establish the contact-site and phospholipid-transfer mechanism mentioned as background in the sentence. (LLM, conf=0.84)

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Knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy.

“knockout of ACBD5 in HeLa and other mammalian cells did not affect pexophagy (Ferdinandusse et al., 2017; Kors et al., 2024).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Kors et al., 2024 sourcePartly supported

  Section 2.6 (p. 9) reports that other studies did not find ACBD5 involved in peroxisome degradation, and Section 3.2 (p. 13) says human ACBD5 does not appear to affect it. The cited paper does not specify ACBD5 knockout in HeLa or other mammalian cells; its own mammalian-cell experiment tested overexpression in H9C2 myoblasts. (LLM, conf=0.84)

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Microcephaly was observed in six RDLKD individuals.

“Microcephaly was observed in six individuals (Ferdinandusse et al., 2017; Al Shamsi et al., 2025), while four patients were significantly underweight (Al Shamsi et al., 2025).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Al Shamsi et al., 2025 sourcePartly supported

  The Case one and Case three sections document microcephaly or a head circumference of −3 SD in two patients, and the Discussion describes microcephaly as a feature of the series. This paper does not establish the cited total of six individuals; that total is attributed jointly to this paper and Ferdinandusse et al. (LLM, conf=0.88)

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VLC-PUFAs are especially important for the normal function of the retina and cerebellum.

“These are especially important for the normal function of the retina and cerebellum (Yeboah et al., 2021), which may account for the more pronounced pathologies observed in these tissues in RDLKD.”

• cites Yeboah et al., 2021 sourcePartly supported

  The section on retinal function says VLC-PUFAs are essential for the overall health and function of the retina and RPE. The section on tissue-specific disorders does not establish the same role in the cerebellum: it says VLC-PUFAs have not been detected in normal brain, while leaving open the possibility that they are rapidly used there. Thus the retinal part is supported, but the cerebellar part is not. (LLM, conf=0.90)

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Organ-specific differences in chain length and number of double bonds in Acbd5-/- mice likely result from the tissue-specific expression of fatty acid elongases and desaturases.

“These organ-specific differences in chain length and number of double bonds likely result from the tissue-specific expression of fatty acid elongases and desaturases (Ferrero et al., 2025).”

• cites Ferrero et al., 2025 sourcePartly supported

  Section 1.2 (pp. 2–3) describes tissue differences in ELOVL expression and substrate preferences, supporting a possible explanation for organ-specific chain lengths. But it says the mechanism producing tissue-specific degrees of unsaturation is unknown, and it does not establish this explanation for Acbd5-/- mice. (LLM, conf=0.88)

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The consistent VLCFA accumulation in ACBD5-deficient cells may be a consequence of impaired palmitoyl-CoA synthesis, which is primarily performed in peroxisomes from C26:0-CoA β-oxidation.

“The consistent VLCFA accumulation may be a consequence of impaired palmitoyl-CoA synthesis, which is primarily performed in peroxisomes from C26:0-CoA β-oxidation (Herzog et al., 2018) but could further be related to reduced membrane contacts between peroxisomes and the ER, both of which cooperate in ether lipid synthesis.”

• cites Herzog et al., 2018 sourcePartly supported

  The Results and Discussion report VLCFA accumulation in ACBD5-deficient fibroblasts. But the Discussion proposes reduced palmitoyl-CoA generation from C26:0-CoA as one possible explanation for decreased ether phospholipids, not for VLCFA accumulation; it also calls limited hexadecanol supply a more probable explanation. (LLM, conf=0.86)

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Both Acbd5-/- models show cerebellar degeneration marked by Purkinje cell loss, pronounced axonal swellings, and demyelination of cerebellar white matter tracts.

“Consistent with these motor deficits, both Acbd5–/– models show cerebellar degeneration marked by Purkinje cell loss, pronounced axonal swellings, and demyelination of cerebellar white matter tracts (Darwisch et al., 2020; Granadeiro et al., 2024), which correlates with the cerebellar symptoms typically observed in RDLKD patients.”

• cites Darwisch et al., 2020 sourcePartly supported

  The Results section ('Acbd5−/− mice develop a progressive degenerative phenotype in the cerebellum') reports Purkinje cell loss, frequent axonal swellings, and slight but significant demyelination in cerebellar homogenates from the mice studied. It does not establish demyelination specifically in cerebellar white matter tracts or findings in both models; its discussion attributes cerebellar-peduncle demyelination to patients, not these mice. (LLM, conf=0.88)

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• cites Granadeiro et al., 2024 sourcePartly supported

  The sections on retina defects and ataxia, giant axon swellings, and CNS demyelination (page numbers unavailable) report Purkinje cell loss, axonal swellings, and cerebellar white-matter demyelination in the Gly357* mouse model. This paper does not establish all three findings in both models named by the citing sentence. (LLM, conf=0.85)

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Another study observed only VLCFA accumulation in fibroblasts from another ACBD5-deficient patient, while ether lipids and DHA were not altered.

“By contrast, Fujiki and coworkers only observed the accumulation of VLCFA in fibroblasts from another ACBD5-deficient patient, while ether lipids and DHA were not altered (Yagita et al., 2017).”

• cites Yagita et al., 2017 sourceSupported

ACBD5-deficient mice develop significant gliosis throughout the white and gray matter of the telencephalon.

“Moreover, their ACBD5-deficient mice developed a significant gliosis throughout the white and gray matter of the telencephaolon, which correlates with the brain degeneration observed in RDLKD patients.”

• cites Granadeiro et al., 2024 sourcePartly supported

  The section “Extensive gliosis underscores CNS pathology in Gly357* mice” reports gliosis in both grey and white matter of the spinal cord by one year of age. It does not establish gliosis throughout the white and grey matter of the telencephalon; the cited sentence places the finding in a different anatomical region. Page numbers were not available in our copy. (LLM, conf=0.90)

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Fatty acids accumulating in membrane phospholipids in the CNS of Acbd5-/- mice exhibit a higher degree of unsaturation compared to those in the liver.

“Additionally, fatty acids accumulating in membrane phospholipids in the CNS exhibit a higher degree of unsaturation compared to those in the liver (Darwisch et al., 2020).”

• cites Darwisch et al., 2020 sourcePartly supported

  The Results section (page unavailable) reports that highly unsaturated fatty acids accumulated in Acbd5−/− cerebellum but not liver, and that these fatty acids were enriched specifically in membrane phosphatidylcholine (PC). The claim broadens that finding from cerebellum to the CNS and from PC to membrane phospholipids generally; the paper reports no major organ-specific difference for phosphatidylethanolamine (PE). (LLM, conf=0.85)

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These mouse models validate the impaired peroxisomal β-oxidation capacity previously demonstrated in patient-derived fibroblasts.

“These models thus validate the impaired peroxisomal β-oxidation capacity previously demonstrated in patient-derived fibroblasts (Ferdinandusse et al., 2017; Yagita et al., 2017).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Yagita et al., 2017 sourceSupported

All analyzed tissues-liver, cerebellum, and spinal cord-show increased incorporation of VLCFAs into phosphatidylcholines in Acbd5-/- mice.

“As expected from elevated VLCFA levels, all analyzed tissues—liver, cerebellum, and spinal cord—show increased incorporation of VLCFAs into phosphatidylcholines.”

• cites Darwisch et al., 2020 sourcePartly supported

  The Results section on lipidomic profiles reports increased VLCFAs in liver and cerebellar phospholipids and describes elevated VLCFA-containing phosphatidylcholines in Acbd5−/− mice. But the Methods section on tissue lipidomics says only liver and cerebellum were analyzed; the paper does not establish increased incorporation into phosphatidylcholines in spinal cord. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Both ACBD5-deficient mouse strains developed retinal dystrophy characterized by photoreceptor cell loss and microglial activation.

“Like human patients, both mouse strains developed retinal dystrophy, characterized by photoreceptor cell loss and microglial activation (Darwisch et al., 2020; Granadeiro et al., 2024).”

• cites Darwisch et al., 2020 sourcePartly supported

  The Results section reports retinal degeneration in the Acbd5−/− mouse strain, with reduced photoreceptor cells and increased microglia. The paper describes one ACBD5-deficient mouse strain, so it does not by itself support the claim that both strains developed this phenotype. No page number is available in our copy. (LLM, conf=0.86)

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• cites Granadeiro et al., 2024 sourcePartly supported

  The section “Loss of Acbd5 causes retina defects and ataxia” reports photoreceptor degeneration in Gly357* mice, supporting retinal dystrophy in the strain studied here. The paper reports microglial activation in the spinal cord, not the retina, and does not establish retinal findings for both mouse strains. (LLM, conf=0.88)

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Fatty acid chain length is governed by a balance between elongation and degradation, a process thought to be regulated at ER-peroxisome contact sites.

“Fatty acid chain length is governed by a balance between elongation and degradation, a process thought to be regulated at ER–peroxisome contact sites (Wanders et al., 2018; Schrader et al., 2020).”

• cites Wanders et al., 2018 sourceCould not verify

  The indexed passages labeled Abstract contain bibliographic information, not the chapter’s discussion. Searches for fatty-acid chain length, elongation and degradation, and ER–peroxisome contact sites returned no passage addressing the claim, so the available copy cannot verify it. (LLM, conf=0.76)

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• cites Schrader et al., 2020 sourceSupported

Neuroinflammation is evident in both ACBD5-deficient mouse models.

“Neuroinflammation, a hallmark of leukodystrophies, is also evident in both mouse models.”

• cites Granadeiro et al., 2024 sourcePartly supported

  The section ‘Extensive gliosis underscores CNS pathology in Gly357* mice’ (page unavailable) reports increased astrocyte reactivity and microgliosis, supporting neuroinflammation in the Gly357* model. The paper’s discussion mentions an Acbd5 tm1a mutant, but the passages found do not establish neuroinflammation in that second model; ‘both mouse models’ is therefore unsupported by this source. (LLM, conf=0.86)

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Different patient-derived cultures from separate research groups identified normal phosphatidylethanolamine-plasmalogen levels.

“It should be noted that, however, different patient derived cultures from separate research groups identified normal phosphatidylethanolamine-plasmalogen levels (Yagita et al., 2017).”

• cites Yagita et al., 2017 sourceSupported

Both Acbd5-/- mouse strains display approximately twofold increases in hexacosanoic acid (C26:0) levels in tissues and plasma, mirroring biochemical abnormalities observed in ACBD5-deficient patients.

“Both Acbd5–/– mouse strains display approximately twofold increases in hexacosanoic acid (C26:0) levels in tissues and plasma, mirroring biochemical abnormalities observed in ACBD5-deficient patients (Darwisch et al., 2020; Granadeiro et al., 2024).”

• cites Darwisch et al., 2020 sourcePartly supported

  The Results section reports elevated C26:0 in the plasma and tissues of the Acbd5−/− mice studied, and the Discussion notes elevated very-long-chain fatty acids in ACBD5-deficient patients. But the Results specify a threefold increase, not approximately twofold, and this paper does not establish the finding for both mouse strains. (LLM, conf=0.90)

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• cites Granadeiro et al., 2024 sourcePartly supported

  The section “Disruption of CNS lipid homeostasis in Gly357* mice” (page unavailable) reports a twofold C26:0 increase in the spinal cords of Gly357* mice. The Discussion (page unavailable) also reports VLCFA accumulation in ACBD5-deficient patients and the other mouse strain, but does not establish a twofold C26:0 increase in both strains across tissues and plasma. (LLM, conf=0.88)

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ELOVL4 is selectively expressed in the skin, testis, and nervous system.

“ELOVL4 is selectively expressed in the skin, testis, and nervous system (Yeboah et al., 2021), and its activity, along with that of CNS-specific desaturases, may partly explain the predominantly neurological phenotype in ACBD5-deficient mice and humans.”

• cites Yeboah et al., 2021 sourcePartly supported

  The tissue-distribution section lists skin, testes, and brain among ELOVL4-expressing tissues. It also lists the retina and Meibomian glands, so the citing sentence's selective-expression description omits sites identified by the source. No page number is provided in the supplied passage. (LLM, conf=0.86)

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In response to siRNA-mediated knockdown of ACBD5 and/or VAP proteins in HeLa cells, reductions in cellular cholesterol levels were reported.

“In response to the siRNA mediated knockdown of ACBD5 and/or VAP proteins in HeLa cells reductions in cellular cholesterol levels were reported (Hua et al., 2017).”

• cites Hua et al., 2017 sourceSupported

Levels of alkyl-diacyl- and alkyl-acylglycerols are approximately doubled in the liver of Acbd5tmn1a mice.

“Notably, levels of alkyl-diacyl- and alkyl-acylglycerols are approximately doubled in the liver (Darwisch et al., 2020).”

• cites Darwisch et al., 2020 sourcePartly supported

  The Results section on lipidomic profiles reports significantly increased liver levels of both alkyldiacylglycerols (TG[O]) and alkylmonoacylglycerols (DG[O]) in Acbd5−/− mice. The Animal breeding section identifies these mice as carrying the Acbd5tm1a allele. Our copy does not state that either lipid level was approximately doubled, so the magnitude is not verified. (LLM, conf=0.85)

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Acbd5tmn1a mice display significantly increased peroxisome numbers in hepatocytes.

“Interestingly, Acbd5tmn1a mice display significantly increased peroxisome numbers in hepatocytes, which may partially compensate for the reduction in peroxisomal β-oxidation capacities and supply (Darwisch et al., 2020).”

• cites Darwisch et al., 2020 sourceSupported

These complex lipid changes are particularly pronounced in the spinal cord of Acbd5Gly357* mice.

“These complex lipid changes are particularly pronounced in the spinal cord of Acbd5Gly357* mice (Granadeiro et al., 2024).”

• cites Granadeiro et al., 2024 sourcePartly supported

  The section ‘Disruption of CNS lipid homeostasis in Gly357* mice’ reports 139 dysregulated lipids in mutant spinal cords and describes the changes as complex. It does not establish that the changes are particularly pronounced in the spinal cord relative to other tissues. (LLM, conf=0.82)

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Loss of ACBD5 can disrupt multiple pathways (e.g., ether lipid, bile acid, or DHA synthesis; balancing VLCFA elongation and breakdown) that rely on the interplay between these organelles.

“Loss of ACBD5 can therefore disrupt multiple pathways (e.g., ether lipid-, bile acid, or DHA synthesis; balancing the equilibrium between VLCFA elongation and breakdown) that rely on the interplay between these organelles (Figure 3; Wanders et al., 2018).”

• cites Wanders et al., 2018 sourceCould not verify

  The available copy contains the chapter title and bibliographic metadata, but no passage addressing ACBD5 or the proposed metabolic effects. Searches for ACBD5, the named pathways, and peroxisomal interactions returned no substantive chapter text, so the claim cannot be checked against this copy. (LLM, conf=0.72)

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Acox1-/- mice show early-onset retinal degeneration marked by photoreceptor loss and shortage of DHA-containing lipids as early as 1 month of age.

“Recent studies have reported early-onset retinal degeneration, marked by photoreceptor loss and shortage of DHA-containing lipids as early as 1 month of age (Boeck et al., 2025).”

• cites Boeck et al., 2025 sourcePartly supported

  The Results (Fig. 4, page not provided) report reduced retinal DHA in Acox1 knockout mice at P30, about one month of age, and the Results on retinal degeneration report impaired rod signaling. But photoreceptor loss at that age is not established: total retinal thickness was unchanged, and the Discussion says thinning of the photoreceptor nuclear layer was observed at five months, not one month. (LLM, conf=0.91)

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VLCFA import into peroxisomes is mediated by the ABC transporters ABCD1 and ABCD2, which have overlapping but distinct substrate preferences.

“Very-long-chain fatty acid import into peroxisomes is mediated by the ABC transporters ABCD1 and ABCD2, which have overlapping but distinct substrate preferences (Tawbeh et al., 2021) (Figure 1).”

• cites Tawbeh et al., 2021 sourceSupported

Acbd2-/- mice show no accumulation of C26:0 in the spinal cord.

“These molecular differences are also reflected in vivo: Acbd1–/– mice exhibit a roughly sixfold increase in C26:0 levels in the spinal cord—approximately three times higher than in Acbd5–/– mice—whereas Acbd2–/– mice show no such accumulation (Pujol et al., 2004; Granadeiro et al., 2024).”

• cites Pujol et al., 2004 sourceSupported
• cites Granadeiro et al., 2024 sourceCould not verify

  The section ‘Disruption of CNS lipid homeostasis in Gly357* mice’ reports a twofold spinal-cord C26:0 increase in Acbd5-mutant mice, not a result for Acbd2−/− mice. The Introduction mentions Abcd1:Abcd2 double-knockout mice but gives no spinal-cord C26:0 measurement for them; a search for Acbd2−/− and Abcd2 knockout C26:0 found no passage establishing the claimed absence of accumulation. Page numbers were not available in our copy. (LLM, conf=0.76)

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Preclinical studies using AAV-mediated delivery of a functional ACBD5 gene have shown significant improvement in disease progression in the Acbd5Gly357* mouse model.

“Gene therapy offers a promising avenue; preclinical studies using adeno-associated virus (AAV)-mediated delivery of a functional ACBD5 gene have shown significant improvement in disease progression in the Acbd5Gly357* mouse model (Granadeiro et al., 2024).”

• cites Granadeiro et al., 2024 sourceSupported

Acbd2-/- mice develop signs of ataxia corresponding to a significant decline in cerebellar Purkinje neurons at the age of 20 months.

“Moreover, Acbd2–/– mice develop signs of ataxia corresponding to a significant decline in cerebellar Purkinje neurons at the age of 20 months, suggesting that the more severe locomotor phenotype is associated with the degeneration of central motor centers (Ferrer et al., 2005).”

• cites Ferrer et al., 2005 sourceSupported

Retina and cerebellum exhibit the highest expression levels of ELOVL4, the elongase responsible for synthesizing VLCFAs.

“Notably, these two tissues exhibit the highest expression levels of ELOVL4, the elongase responsible for synthesizing VLCFAs (Yeboah et al., 2021; Sherry et al., 2017).”

• cites Yeboah et al., 2021 sourcePartly supported

  The section on ELOVL4 tissue distribution (page unavailable) says ELOVL4 synthesizes very-long-chain fatty acids and is expressed in the retina and brain. It identifies the sites of highest expression within the eye, but does not say that the retina and cerebellum have the highest expression levels among tissues. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Sherry et al., 2017 sourcePartly supported

  The Introduction identifies ELOVL4 as the enzyme needed to synthesize very-long-chain fatty acids and lists both brain and retina among tissues where it is expressed. The Results (Distribution of ELOVL4 in specific brain regions; page unavailable) report that cerebellar granule-layer neurons had the most intense labeling of any cells in the brain. The paper does not establish that the retina and cerebellum are the two highest-expressing tissues overall. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

DHA depletion may be a key driver of CNS pathology.

“Importantly, dietary DHA supplementation significantly ameliorated disease progression in both Mfp2–/– and Acox1–/– models, suggesting that DHA depletion may be a key driver of CNS pathology (Swinkels et al., 2023; Boeck et al., 2025).”

• cites Swinkels et al., 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Boeck et al., 2025 sourcePartly supported

  The Results report that DHA alone significantly improved cone signaling in Acox1 knockout mice, but did not significantly change rod signaling; DHA plus ARA improved rod signaling. The Discussion links depleted DHA to retinal dysfunction, supporting a possible role in neural retinal pathology, but this paper does not establish DHA depletion as a key driver of CNS pathology more broadly or show that DHA alone significantly ameliorated overall disease progression. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

ACBD5 may have a more complex role at the peroxisomal membrane.

“Its coiled-coil domain mediates homo-oligomerization, but also hetero-oligomerization with ACBD4 (Costello et al., 2023), suggesting a more complex role at the peroxisomal membrane.”

• cites Costello et al., 2023 sourceSupported

Dietary DHA supplementation significantly ameliorated disease progression in both Mfp2-/- and Acox1-/- models.

“Importantly, dietary DHA supplementation significantly ameliorated disease progression in both Mfp2–/– and Acox1–/– models, suggesting that DHA depletion may be a key driver of CNS pathology (Swinkels et al., 2023; Boeck et al., 2025).”

• cites Swinkels et al., 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Boeck et al., 2025 sourcePartly supported

  The Results section (page unavailable) reports that DHA-fed Acox1 knockout mice had significantly improved retinal cone signaling from P30 to P60, while rod signaling did not change significantly. Boeck et al. thus support a benefit for a retinal measure in the Acox1 model, but not the broader claim that DHA significantly ameliorated disease progression. The paired Mfp2 claim is associated with the other citation, not established by this paper. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The more severe locomotor phenotype in Acbd2-/- mice is associated with degeneration of central motor centers.

“Moreover, Acbd2–/– mice develop signs of ataxia corresponding to a significant decline in cerebellar Purkinje neurons at the age of 20 months, suggesting that the more severe locomotor phenotype is associated with the degeneration of central motor centers (Ferrer et al., 2005).”

• cites Ferrer et al., 2005 sourceSupported

ACBD4 expression can compensate for the loss of ACBD5 in peroxisome-ER tethering and VLCFA β-oxidation in cell culture.

“As ACBD4 expression can compensate for the loss of ACBD5 in peroxisome-ER tethering and VLCFA β-oxidation in cell culture (Costello et al., 2023), pharmacological upregulation of ACBD4 expression may be an approach to overcome loss of ACBD5.”

• cites Costello et al., 2023 sourceSupported

A widespread CNS leukodystrophy has been observed in all reported ACBD5-deficient patients.

“a widespread CNS leukodystrophy has been observed in all reported ACBD5-deficient patients”

The remaining homozygous patients, all lacking functional ACBD5 protein, typically present with both ophthalmological and neurological symptoms shortly after birth.

“The remaining homozygous patients, all of whom lack functional ACBD5 protein expression, typically present with both ophthalmological and neurological symptoms shortly after birth.”

Of the 11 known ACBD5 deficient patients, most exhibit impaired peroxisomal β-oxidation of VLCFA, reflected by elevated plasma levels of hexacosanoic acid (C26:0).

“Of the 11 known ACBD5 deficient patients, most exhibit impaired peroxisomal β-oxidation of VLCFA, reflected by elevated plasma levels of hexacosanoic acid (C26:0) (Table 1 and Supplementary Table 1).”

C22 plasma concentrations in ACBD5-deficient patients show variable changes: one elevated, two decreased, and two normal.

“The same is observed for C22 with one patient having elevated C22, two decreased, and two normal.”

Functional complementation of ACBD5-deficient patient cells with wild-type ACBD5 restored normal VLCFA metabolism.

“The functional complementation of patient cells with wild-type ACBD5, which restored normal VLCFA metabolism, confirms the causative role of ACBD5 defects in compromised VLCFA handling (Table 2).”

C24 plasma concentrations in ACBD5-deficient patients show variable changes: two elevated, two decreased, and two normal.

“Conversely, C24 plasma concentrations show variable changes, with two patients having elevated C24, two decreased, and two normal.”

Out of nine ACBD5-deficient patients measured for C26 plasma concentration, six displayed elevated levels while three were normal.

“Out of nine patients measured for C26 plasma concentration, six displayed elevated levels while three patients were normal.”

Oxidation of pristanic acid in ACBD5-deficient patient fibroblasts was only marginally raised.

“The oxidation of the breakdown product of phytanic acid, pristanic acid, was only marginally raised, indicating functionality of the peroxisomal β-oxidation pathway itself.”

All peroxisomal enzymes except ACOX1 were found to be in normal ranges in ACBD5-deficient patient fibroblasts.

“Furthermore, all peroxisomal enzymes except for ACOX1 were found to be in normal ranges (Table 2).”

In vitro, Acbd5-/- cortical neurons treated with tetracosanoic acid methyl ester (C24) displayed reduced actin dynamics.

“In vitro, Acbd5–/– cortical neurons treated with tetracosanoic acid methyl ester (C24) displayed reduced actin dynamics, suggesting that lipidomic imbalances may impair cytoskeletal regulation—potentially underlying the neurological manifestations of ACBD5 deficiency.”

The corticospinal motor tracts appear to be particularly susceptible in most currently described RDLKD cases.

“the corticospinal motor tracts appearing to be particularly susceptible in most currently described RDLKD cases”

Widespread grey matter degeneration is potentially relatively rare in RDLKD.

“indicating that widespread grey matter degeneration is potentially relatively rare.”

RDLKD appears to be a multifactorial disorder leading to a mosaic pathology combining symptoms caused by disruption of several pathways.

“Hence, RDLKD appears to be a multifactorial disorder leading to a mosaic pathology, combining symptoms caused by the disruption of several pathways.”

Absence or dysfunction of ACBD5 causes the peroxisomal disorder RDLKD.

“The absence or dysfunction of the peroxisomal membrane protein Acyl-CoA Binding Domain-Containing Protein 5 (ACBD5) is the cause of the most recently discovered peroxisomal disorder “Retinal Dystrophy with Leukodystrophy” (RDLKD).”

ACBD5 is a peroxisomal tethering protein facilitating membrane contacts with the endoplasmic reticulum.

“the first identified peroxisomal tethering protein facilitating membrane contacts with the endoplasmic reticulum (ER)”

Delayed language development was reported in five ACBD5-deficient patients.

“and delayed language development in five (Ferdinandusse et al., 2017; Bartlett et al., 2021; Gorukmez et al., 2022; Hasturk et al., 2024; Al Shamsi et al., 2025; Supplementary Table 1).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source
• cites Bartlett et al., 2021 sourceNot checked — no full text of the source
• cites Gorukmez et al., 2022 sourceNot checked — no full text of the source

RDLKD may have a neuropsychiatric component.

“suggesting a possible neuropsychiatric component to RDLKD”

Febrile convulsions were reported in two ACBD5-deficient patients during early childhood.

“febrile convulsions were reported in two others already during early childhood (Gorukmez et al., 2022)”

• cites Gorukmez et al., 2022 sourceNot checked — no full text of the source

One RDLKD patient was born with a cleft palate.

“Additionally, one patient was born with a cleft palate (Ferdinandusse et al., 2017; Supplementary Table 1).”

• cites Ferdinandusse et al., 2017 sourceNot checked — no full text of the source

ACOX1 may be raised in ACBD5-deficient fibroblasts as a response to the over-abundance of distinct VLCFAs activating PPARs.

“ACOX1, the key enzyme in peroxisomal β-oxidation (Figure 1), may be raised as a response to the over-abundance of distinct VLCFAs activating PPARs, suggesting that peroxisomes are functional but the lack of ACBD5 impedes peroxisomal VLCFA availability for β-oxidation.”

In RDLKD, current MRI data do not suggest a consistent regional pattern of white matter lesions.

“while in RDLKD, current MRI data do not suggest a consistent regional pattern.”

ACBD5 defects have a causative role in compromised VLCFA handling.

“confirms the causative role of ACBD5 defects in compromised VLCFA handling”

Differences in retinal and cerebellar pathology between X-ALD and RDLKD may stem from distinct lipid metabolic alterations.

“The differences in retinal and cerebellar pathology between X-ALD and RDLKD may stem from distinct lipid metabolic alterations.”

RDLKD bears partial resemblance to Refsum disease, which features retinitis pigmentosa and cerebellar ataxia.

“With respect to its phenotype, RDLKD bears partial resemblance to Refsum disease, which also features retinitis pigmentosa and cerebellar ataxia (Ruether et al., 2010).”

• cites Ruether et al., 2010 sourceNot checked — no full text of the source

In X-ALD, optic nerve degeneration and inflammation are primary drivers of visual impairment.

“In X-ALD, optic nerve degeneration and inflammation are primary drivers, whereas in RDLKD, retinal degeneration—including loss of RPE—is the principal cause.”

The broader lipid profile including VLC-PUFA accumulation may account for the more pronounced retinal and cerebellar pathologies in RDLKD.

“which may account for the more pronounced pathologies observed in these tissues in RDLKD.”

ACBD5 deficiency (RDLKD) presents a complex and variable clinical phenotype, reflecting a broad spectrum of disease severity.

“In summary, ACBD5 deficiency (RDLKD) presents a complex and variable clinical phenotype, reflecting a broad spectrum of disease severity (Supplementary Table 1).”

RDLKD has broad phenotypic variability and severity.

“highlighting the broad phenotypic variability/severity of the disorder.”

In X-ALD, retinal pathology typically manifests only in the severe cerebral form of the disease and is rarely observed in the milder adrenomyelopathy.

“Moreover, in X-ALD, retinal pathology typically manifests only in the severe cerebral form of the disease and is rarely observed in the milder adrenomyelopathy (Bianchi-Marzoli et al., 2021).”

• cites Bianchi-Marzoli et al., 2021 sourceNot checked — no full text of the source

Fibroblast data from RDLKD patients indicate a broader lipid profile that includes an accumulation of VLC-PUFAs.

“However, fibroblast data from RDLKD patients indicate a broader lipid profile that includes an accumulation of VLC-PUFAs.”

In X-ALD, specifically saturated and monounsaturated VLCFAs accumulate in phospholipids.

“In X-ALD, specifically saturated and monounsaturated VLCFAs accumulate in phospholipids.”

In RDLKD, retinal degeneration including loss of RPE is the principal cause of visual impairment.

“whereas in RDLKD, retinal degeneration—including loss of RPE—is the principal cause.”

The peroxisomal β-oxidation pathway itself is functional in ACBD5-deficient fibroblasts.

“indicating functionality of the peroxisomal β-oxidation pathway itself.”

RDLKD shares certain biochemical and pathological features with X-ALD.

“Biochemically (see section “2.4 Biochemical and cellular alterations in ACBD5-deficient patients”) and pathologically, RDLKD shares certain features with X-ALD, the most common peroxisomal disorder.”

Unlike Refsum disease, ACBD5-deficient patients typically have normal phytanoyl-CoA plasma levels.

“However, unlike Refsum disease, which stems from impaired branched-chain fatty acid metabolism, ACBD5-deficient patients typically have normal phytanoyl-CoA plasma levels.”

Cerebellar degeneration in Acbd5-/- models correlates with the cerebellar symptoms typically observed in RDLKD patients.

“which correlates with the cerebellar symptoms typically observed in RDLKD patients.”

To date, insights into the cellular and metabolic consequences of ACBD5 deficiency in humans are derived exclusively from fibroblast cultures and immortalized cell lines, where ACBD5 was inactivated using CRISPR-Cas9 technology.

“To date, insights into the cellular and metabolic consequences of ACBD5 deficiency in humans are derived exclusively from fibroblast cultures and immortalized cell lines, where ACBD5 was inactivated using CRISPR-Cas9 technology.”

Knowledge of ACBD5's role in terminally differentiated cells such as neurons and in complex tissues remains limited.

“As a result, knowledge of ACBD5’s role in terminally differentiated cells—such as neurons—and in complex tissues remains limited.”

Lipidomic imbalances may impair cytoskeletal regulation, potentially underlying the neurological manifestations of ACBD5 deficiency.

“suggesting that lipidomic imbalances may impair cytoskeletal regulation—potentially underlying the neurological manifestations of ACBD5 deficiency.”

Gliosis in ACBD5-deficient mice correlates with the brain degeneration observed in RDLKD patients.

“which correlates with the brain degeneration observed in RDLKD patients.”

Mfp2-/- mice display reduced levels of DHA in membrane lipids.

“Notably, Mfp2–/– mice also display reduced levels of DHA in membrane lipids, a feature not observed in Acbd5–/– mice.”

This may explain why Acbd5-/- mice are unable to compensate for CNS ether lipid deficits through hepatic export of surplus alkylglycerols.

“This may explain why Acbd5–/– mice are unable to compensate for CNS ether lipid deficits through hepatic export of surplus alkylglycerols.”

DHA synthesis or dietary uptake appears sufficient to maintain adequate levels in membrane lipids in ACBD5 deficiency.

“Accordingly, DHA synthesis or dietary uptake appears sufficient to maintain adequate levels in membrane lipids.”

ELOVL4 activity along with CNS-specific desaturases may partly explain the predominantly neurological phenotype in ACBD5-deficient mice and humans.

“and its activity, along with that of CNS-specific desaturases, may partly explain the predominantly neurological phenotype in ACBD5-deficient mice and humans.”

This compensation could help explain why the Acbd5-/- mice, despite marked neuropathology, often survive beyond 1 year.

“This compensation could help explain why the Acbd5–/– mice, despite marked neuropathology, often survive beyond 1 year.”

Lipidomic analyses of Mfp2-/- retinas reveal significant accumulation of VLC-PUFAs in the CNS.

“Lipidomic analyses of Mfp2–/– retinas, which also exhibit early and severe degeneration, reveal significant accumulation of VLC-PUFAs in the CNS (Das et al., 2021).”

• cites Das et al., 2021Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Increased peroxisome numbers in hepatocytes may partially compensate for the reduction in peroxisomal β-oxidation capacities and supply in Acbd5tmn1a mice.

“which may partially compensate for the reduction in peroxisomal β-oxidation capacities and supply”

Disruption of ER-peroxisome contact zones in ACBD5-deficient cells may lead to sustained fatty acid elongation at the ER.

“Disruption of these contact zones in ACBD5-deficient cells may lead to a sustained fatty acid elongation at the ER (Figure 3).”

Acbd5-/- mice do not show reduced levels of DHA in membrane lipids.

“Notably, Mfp2–/– mice also display reduced levels of DHA in membrane lipids, a feature not observed in Acbd5–/– mice.”

Compensatory mechanisms, possibly via upregulated DHA synthesis, may maintain DHA levels in Acbd5-/- mice.

“suggesting compensatory mechanisms, possibly via upregulated DHA synthesis.”

This can result in an accumulation of ultra-long chain fatty acids in tissues expressing ELOVL4.

“This can result in an accumulation of ultra-long chain fatty acids in tissues expressing ELOVL4—the only elongase capable of extending fatty acids beyond C32.”

DHA synthesis requires three consecutive rounds of elongation and desaturation at the ER followed by a single, final chain-shortening step by peroxisomal β-oxidation.

“Originating from linolenic acid, the synthesis of DHA requires three consecutive rounds of elongation and desaturation at the ER followed by a single, final chain-shortening step by peroxisomal β-oxidation (Wanders et al., 2023).”

• cites Wanders et al., 2023 sourceNot checked — no full text of the source

Onset of locomotor symptoms was observed significantly earlier in Abcd2-/- than in Abcd1-/- mice.

“In contrast, onset of locomotor symptoms was observed significantly earlier in Abcd2–/– than in Abcd1–/– mice.”

Straight-chain VLCFAs likely play a minor role in Acbd5-/- disease progression.

“Since Acbd1–/– mice accumulate the highest levels of straight-chain VLCFAs without developing CNS pathology, these lipid species likely play a minor role in Acbd5–/– disease progression.”

Key biochemical abnormalities, affected tissues, and the progressive nature of the phenotype show substantial similarities between mice and humans.

“Nevertheless, the key biochemical abnormalities, affected tissues, and the progressive nature of the phenotype—which ultimately leads to considerable severity—show substantial similarities between mice and humans.”

Leukodystrophy, motor impairments combined with early ophthalmological alterations during childhood appear to be key features of ACBD5 deficiency.

“Leukodystrophy, motor impairments combined with early ophthalmological alterations during childhood appear to be key features of the disease and combined with elevated VLCFA plasma levels, should prompt consideration of RDLKD.”

The dual role of ACBD5 may contribute to the disorder's heterogeneity.

“Additionally, the dual role of ACBD5 may contribute to the disorder’s heterogeneity.”

Species-specific differences in liver metabolism, retinal cell morphology, and CNS complexity limit the direct translatability of findings from mice to patients.

“However, species-specific differences in liver metabolism, retinal cell morphology, and CNS complexity limit the direct translatability of findings from mice to patients.”

ACBD5 deficiency presents with a broad spectrum of disease severity, like other peroxisomal single-enzyme deficiencies that do not entirely block a metabolic pathway such as X-ALD.

“Like other peroxisomal single-enzyme deficiencies that do not entirely block a metabolic pathway—such as X-ALD—ACBD5 deficiency presents with a broad spectrum of disease severity.”

Variability in ACBD5 deficiency may reflect individual responses to metabolic alterations influenced by the patient's genetic background.

“This variability may reflect individual responses to metabolic alterations influenced by the patient’s genetic background.”

Accumulation of VLC-PUFAs may be more relevant to Acbd5-/- disease progression.

“Instead, the accumulation of VLC-PUFAs may be more relevant.”

Only ABCD2 appears to have substrate specificity for VLC-PUFAs, including DHA.

“Both transporters can import saturated and monounsaturated VLCFAs, but only ABCD2 appears to have substrate specificity for VLC-PUFAs, including DHA.”

Both ABCD1 and ABCD2 can import saturated and monounsaturated VLCFAs.

“Both transporters can import saturated and monounsaturated VLCFAs, but only ABCD2 appears to have substrate specificity for VLC-PUFAs, including DHA.”

The accumulation of VLCFAs, their subsequent incorporation into phospholipids, and altered lipid spectrum appears to correlate well with the neurological abnormalities in ACBD5 deficiency.

“The accumulation of VLCFAs, their subsequent incorporation into phospholipids, and altered lipid spectrum appears to correlate well with the neurological abnormalities in ACBD5 deficiency.”

Early retinal and cerebellar symptoms observed in RDLKD patients align with cytological abnormalities seen in Acbd5-deficient mouse models.

“In this context, the early retinal and cerebellar symptoms observed in RDLKD patients align with cytological abnormalities seen in Acbd5-deficient mouse models.”

Marked accumulation of VLC-PUFAs in cerebellar phospholipids of Acbd5-deficient mice may suggest their involvement in RDLKD pathogenesis.

“Given ELOVL4’s essential role in VLC-PUFA synthesis, the marked accumulation of these fatty acids in cerebellar phospholipids of Acbd5-deficient mice may suggest their involvement in RDLKD pathogenesis.”

Treatment of RDLKD patients before or at the beginning of symptom development might more effectively ameliorate disease progression.

“Considered that the stem cell therapy was administered considerably after the onset of the disease pathology (at the age of 3), a treatment of RDLKD patients before or at the beginning of the development of symptoms might more effectively ameliorate disease progression.”

The true prevalence of RDLKD is likely underestimated due to current diagnostic limitations.

“Such efforts will not only improve diagnostic accuracy but also enhance our understanding of the RDLKD phenotype spectrum and reveal its true prevalence, which is likely underestimated due to current diagnostic limitations.”

One reported RDLKD patient received autologous intrathecal hematopoietic stem cell transplantation at age 29, leading to transient, partial improvement of vision, speech, and locomotor abilities.

“One of the reported RDLKD patients received an autologous intrathecal hematopoietic stem cell transplantation at the age of 29, which lead to a transient, partial improvement of vision, speech and locomotor abilities (Bartlett et al., 2021).”

• cites Bartlett et al., 2021 sourceNot checked — no full text of the source

Standard neonatal screening may miss affected individuals because fatty acid profiles can appear normal in some ACBD5-deficient patients.

“However, standard neonatal screening may miss affected individuals, as fatty acid profiles can appear normal in some ACBD5-deficient patients.”