Question 1 of 10

    AMACR Deficiency (Alpha-Methylacyl-CoA Racemase Deficiency)

    α-Methylacyl-CoA racemase (AMACR) deficiency is an inherited condition that leads to functional impairment of the cellular peroxisomes and elevated levels of pristanic acid, phytanic acid, and C27-bile acid intermediates.

    Presentation

    AMACR deficiency manifests with a varying clinical picture. A more definitive establishment of a presenting pattern has not been rendered possible, due to the lack of clinical experience with such a rare disease.

    The clinical picture admittedly resembles that of Refsum disease with sensorimotor neuropathy. The latter usually presents during adulthood and can be accompanied by pigmentary retinopathy, although this is not always the case [21]. Symptoms associated with the central or peripheral nervous system predominate and generally include encephalopathy, hearing and visual impairment or complete loss, epilepsy and cerebellar ataxia, although dysfunctions in other organs have also been reported, such as end-stage liver disease, depression and rhabdomyolysis [22] [23] [24] [25] [26]. Growth is usually hindered in patients affected by AMACR.

    Entire body system
    Epilepsy
    • Part of the Oxford Textbooks in Clinical Neurology (OTCN) series, this volume covers the scientific basis, clinical diagnosis, and treatment of epilepsy and epileptic seizures.[books.google.de]
    • Metabolic disorders and epilepsy.[euroepinomics.wordpress.com]
    • Comprehensive Epilepsy Panel that also includes the following genes: HSD17B10 TREX1 MTHFR ADAR ALDH7A1 ATRX ARG1 BTD ARX CACNB4 And 184 more, More info about this panel Idiopathic Generalized and Focal Epilepsy Panel Panel By Blueprint Genetics in Finland[mendelian.co]
    • Entire body system Epilepsy Symptoms associated with the central or peripheral nervous system predominate and generally include encephalopathy, hearing and visual impairment or complete loss, epilepsy and cerebellar ataxia, although dysfunctions in other[symptoma.com]
    • Klinické symptomy: senzorimotorická neuropatie, retinitis pigmentosa, epilepsie, hepatální dysfunkce.[enclabmed.cz]
    Weakness
    • Other features of AMACR deficiency may include weakness and loss of sensation in the limbs due to nerve damage (sensorimotor neuropathy), muscle stiffness (spasticity), and difficulty coordinating movements (ataxia).[ghr.nlm.nih.gov]
    • This disorder leads to a variety of neurological problems that begin in adulthood, including gradual loss in intellectual functioning (cognitive decline), seizures, and weakness and loss of sensation in the limbs due to nerve damage (sensorimotor neuropathy[selfdecode.com]
    • Muscle Weakness (Myopathy, Muscular Dystrophy) that also includes the following genes: ETFA DYNC1H1 MTO1 PYGM TTR HSPG2 LPIN1 MATR3 SYNE2 MEGF10 And 169 more, More info about this panel Epilepsy Panel By Medizinisch Genetisches Zentrum München MGZ München[mendelian.co]
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  • neurologic
    Ataxia
    • Kearns-Sayre syndrome is due to deletion of mitochondrial DNA (mtDNA). 2b(iv) Ataxia Friedreich ataxia is characterized by slowly progressive ataxia with onset usually before the age of 25 years typically associated with depressed tendon reflexes, dysarthria[refsumdisease.org]
    • AMACR mutations cause late-onset autosomal recessive cerebellar ataxia.[ghr.nlm.nih.gov]
    • [ghr.nlm.nih.gov] more... neurologic Ataxia AMACR mutations cause late-onset autosomal recessive cerebellar ataxia .[symptoma.com]
    • NNNNNo apparent phenotype; however, beyond age 15 months, areflexia ataxia, hyperactivity, slower nerve conduction, axonal loss in the spinal cord, and Purkinje cell death Ehhadh Lbf/mfp1-NNNNNNo phenotypic abnormalities Slc27a2 Vlcs-NNNNNNo phenotypic[216.92.14.62]
    • Bilateral single transverse palmar creases 100% Hepatomegaly 100% Frontal bossing 100% Encephalopathy 100% Seizures 100% Cholestasis 100% Iris hypopigmentation 100% Autosomal recessive inheritance 100% Biliary tract abnormality 66% Visual impairment 66% Ataxia[mendelian.co]
    Cognitive Deficit
    • Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.[science.gov]
    Encephalopathy
    • […] have also been reported [www.symptoma.com] Encephalopathy In general, patients display neurological sequelae, including encephalopathy , peripheral neuropathy; cholestasis has also been observed.[symptoma.com]
    • Consequently, patients with Amacr deficiency accumulate C27-bile acid intermediates, pristanic and phytanic acid and display sensorimotor neuropathy, seizures and relapsing encephalopathy.[agris.fao.org]
    • We describe a 45-year-old male with a history of seizures who presented with relapsing encephalopathy.[mayoclinic.pure.elsevier.com]
    • At the age 53, the patient also had acute encephalopathy with lack of speech (aphasia) and weakness of her right arm.[euroepinomics.wordpress.com]
    • They may also have acute episodes of brain dysfunction (encephalopathy) similar to stroke, involving altered consciousness and areas of damage (lesions) in the brain.[ghr.nlm.nih.gov]
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  • gastrointestinal
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  • musculoskeletal
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  • Eyes
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  • Ears
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  • Workup

    Peroxisomal disorders typically involve alterations in the cerebral structure, which can be revealed via a magnetic resonance imaging scan. Brain atrophy and neocortical dysplasia featuring perisylvian polymicrogyria and frontoparietal pachygyria are the predominant changes that are observed through the MRI scan [27]. The structures most commonly affected include the basal ganglia, pons, and cerebral peduncles, without a definite pathophysiologic explanation.

    More specifically, as in all peroxisomal disorders, characteristic findings in an MRI scan of a patient with AMACR deficiency involve the following:

    • White matter irregular structure: atrophic locations in the central cerebellar region and dentate nucleus, with the same pattern that is observed in X-linked adrenoleukodystrophy, is frequently depicted. Another possibility is the progressive cerebellar atrophy with an abnormally shaped parietooccipital white matter region; the same abnormality is revealed in the MRI scans of individuals with rhizomelic chondrodysplasia punctata.
    • Neocortical dysplasia, irregular deep central sulcus.
    • T2-weighted increased thalamic signal, cerebral peduncles, and pons.

    Biochemical analysis of blood and urine, as well as fibroblast cultures and genetic testing, can further contribute to diagnosing AMACR deficiency.

    Imaging

    MR
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  • Treatment

    Given that the levels of pristanic and phytanic acid greatly exceed normal values in patients with AMACR deficiency, patients are required to eliminate any source of these two types of acid from their diet. Another suggestion has been the reduction of plasma phytanic acid by plasma exchange; none of the two aforementioned therapeutic options has evinced a definitive contribution to the treatment of AMACR deficiency [28]. Most patients receive cholic acid on a long-term basis, which may not cure the disorder, but leads to the normalization of hepatic enzymes and hinders the aggravation of symptomatology.

    Prognosis

    AMACR deficiency is a rare disorder that has been documented as few as 7 times up to this day. Due to the lack of sufficient statistic data, a unified prognosis cannot be determined. The overall course of some of the documented patients, however, is described below:

    • A study by Ferdinandusse documented 3 patients with AMACR deficiency: two of them were affected by sensory motor neuropathy arising in adulthood, with one of them also being affected by pigmentary retinopathy, epileptic seizures, migraines and depression [6]. The third patient, still in childhood, did not display any symptoms related to an AMACR deficiency but was affected by the Niemann-Pick disease, type C.
    • The second group of patients was later described by Setchell [19]: two siblings, who were both affected by AMACR deficiency, exhibited the same genetic mutation with the first three patients described in the former paragraph. Their clinical picture, however, varied: they presented with coagulopathy, liver disease, cholestatic episodes and vitamin deficiency during the first days of their lives. A previous sibling had died at the age of 5 months old and, following the transplantation of their liver to a 2-year old child, the latter exhibited signs of AMACR deficiency, leading to the conclusion that the deceased sibling has also been affected by the condition. The child who received the liver transplant was treated with ursodeoxycholic acid; during follow-up, they remained in good health for the next 8 years, still under treatment with the medication [20].

    Consequently, based on the data that is available up to this day, it can be said that identical genetic mutations can lead to AMACR with a varying clinical picture, age of onset and general prognosis .

    Complications

    Cholestasis
    • Lykavieris P, Bernard O, Hadchouel M: Neonatal cholestasis in childhood.[content.karger.com]
    • Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs.[rarediseases.org]
    • This homozygous mutation is associated with a variable phenotype ranging from neonatal cholestasis to late-onset sensorimotor neuropathy.[mayoclinic.pure.elsevier.com]
    • Babies with this disorder have cholestasis, which is a reduced ability to produce and release a digestive fluid called bile.[selfdecode.com]
    • Patients manifest neonatal jaundice, intrahepatic cholestasis and bile duct deficiency.[ab-y-ss.com]
    Depression
    • Name Alpha-Methylacyl-Coa Racemase Deficiency Synonyms AMACR DEFICIENCY Classification genetic, metabolism, neurological, hepatic Phenotypes Sensorimotor neuropathy ; Depressivity ; Status epilepticus ; Ataxia ; Autosomal recessive inheritance ; Spasticity[m.mousephenotype.org]
    • […] peripheral nervous system predominate and generally include encephalopathy , hearing and visual impairment or complete loss, epilepsy and cerebellar ataxia , although dysfunctions in other organs have also been reported, such as end-stage liver disease , depression[symptoma.com]
    • Kearns-Sayre syndrome is due to deletion of mitochondrial DNA (mtDNA). 2b(iv) Ataxia Friedreich ataxia is characterized by slowly progressive ataxia with onset usually before the age of 25 years typically associated with depressed tendon reflexes, dysarthria[refsumdisease.org]
    • 100% Encephalopathy 100% Seizures 100% Cholestasis 100% Iris hypopigmentation 100% Autosomal recessive inheritance 100% Biliary tract abnormality 66% Visual impairment 66% Ataxia 66% Spasticity 66% Sensorimotor neuropathy 66% Phenotypic variability 66% Depression[mendelian.co]
    • The neurologic picture comprises severe psychomotor retardation, profound hypotonia with depressed deep tendon reflexes (DTRs), neonatal seizures, and impaired hearing.[emedicine.medscape.com]
    Fat-Soluble Vitamin Deficiency
    • This disorder has also been reported in infants who present with severe fat and fat-soluble vitamin deficiencies and mild cholestasis.[rarediseases.org]
    Liver Disease
    • If untreated, progressive liver disease occurs.[rarediseases.org]
    • Make optimal use of the newest techniques, technologies, and treatments with Sleisenger and Fordtran's Gastrointestinal and Liver Disease - the indispensable information source in this broad field![books.google.de]
    • Lee WS, Sokol RJ: Liver disease in mitochondrial disorders.[content.karger.com]
    • Bile acid synthetic defects and liver disease : a comprehensive review.[symptoma.com]
    • disease and early death mThb Thiolase B-NNNNNNo phenotypic abnormalities Cat CatalaseAcatalasemiaNNNNNNo phenotypic abnormalities except for increased susceptibility to trauma-induced dysfunction of brain mitochondria[216.92.14.62]
    Migraine
    • Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging.[ab-y-ss.com]
    • AMACR DEFICIENCY Classification genetic, metabolism, neurological, hepatic Phenotypes Sensorimotor neuropathy ; Depressivity ; Status epilepticus ; Ataxia ; Autosomal recessive inheritance ; Spasticity ; Pigmentary retinopathy ; Phenotypic variability ; Migraine[m.mousephenotype.org]
    • People with AMACR deficiency may have a gradual loss in intellectual functioning (cognitive decline), seizures, and migraines.[ghr.nlm.nih.gov]
    • [www.symptoma.com] Migraine People with AMACR deficiency may have a gradual loss in intellectual functioning (cognitive decline), seizures, and migraines .[symptoma.com]
    Neurological Disorder
    • Originally, the disorder was believed only to be a neurological disorder of abnormal fat (lipid) storage not associated with liver disease.[rarediseases.org]
    • We here consider the role of L- serine in neurological disorders and its potential as a therapeutic agent.[science.gov]
    Neuropathy
    • The third patient was a child without neuropathy.[nature.com]
    • Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy.[ghr.nlm.nih.gov]
    • Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging.[mendelian.co]
    • […] epileptic seizures, migraines [www.symptoma.com] Neuropathy The clinical picture admittedly resembles that of Refsum disease with sensorimotor neuropathy .[symptoma.com]
    • This homozygous mutation is associated with a variable phenotype ranging from neonatal cholestasis to late-onset sensorimotor neuropathy.[mayoclinic.pure.elsevier.com]
    Peripheral Neuropathy
    • It is characterized by retinitis pigmentosa resulting in progressive visual failure, learning difficulties, a peripheral neuropathy, and hypogonadism.[monarchinitiative.org]
    • [ghr.nlm.nih.gov] Peripheral Neuropathy In general, patients display neurological sequelae, including encephalopathy, peripheral neuropathy ; cholestasis has also been observed.[symptoma.com]
    • Peripheral neuropathy was diagnosed age 57.[ojrd.biomedcentral.com]
    • A few years later, the patient was also diagnosed with peripheral neuropathy.[euroepinomics.wordpress.com]
    • Hereditary peripheral neuropathies: clinical forms, genetics, and molecular mechanisms .[nature.com]
    Retinopathy
    • Kearns-Sayre syndrome (KSS) is defined by the triad of onset before age 20 years, pigmentary retinopathy, and progressive external ophthalmoplegia (PEO).[refsumdisease.org]
    • RP N/A RP No RP degenera-tive retino-pathy N/A pigmentary retinopathy pigmentary retinopathy pigmentary retinopathy DM II N/A N/A N/A N/A N/A N/A N/A No Yes Yes Additional Features primary hypogonadism, migraine migraine cataract, migraine, hyperreflexia[ojrd.biomedcentral.com]
    • Alpha-Methylacyl-Coa Racemase Deficiency Synonyms AMACR DEFICIENCY Classification genetic, metabolism, neurological, hepatic Phenotypes Sensorimotor neuropathy ; Depressivity ; Status epilepticus ; Ataxia ; Autosomal recessive inheritance ; Spasticity ; Pigmentary retinopathy[m.mousephenotype.org]
    • [www.symptoma.com] Retinopathy The latter usually presents during adulthood and can be accompanied by pigmentary retinopathy , although this is not always the case.[symptoma.com]
    • In addition, they may develop myocarditis, neuropathy, osteosclerosis, and retinopathy as a result of oxalate deposits in various organs.[emedicine.medscape.com]
    Rhabdomyolysis
    • Disorder / Myalgia / Rhabdomyolysis Panel By Medizinisch Genetisches Zentrum München MGZ München in Germany.[mendelian.co]
    • […] as end-stage liver disease, depression and rhabdomyolysis [www.symptoma.com] more...[symptoma.com]
    • PubMed View Article Google Scholar Kapina V, Sedel F, Truffert A, Horvath J, Wanders RJ, Waterham HR, Picard F: Relapsing rhabdomyolysis due to peroxisomal alpha-methylacyl-coa racemase deficiency.[ojrd.biomedcentral.com]
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  • Etiology

    Peroxisomes are small organelles that are found in the cytoplasm and mediate the metabolism of multiple lipids, including branched fatty acids (pristanic and phytanic acid). They also take part in the process of bile acid production.

    The completion of specific steps in both procedures require the presence of alpha-methyl-acyl-CoA racemase (AMACR); its deficiency leads to the accumulation of intermediate R-isomers of pristanic acid, as well as di- and tri hydrocholestanoic acids (DHCA and THCA) which are intermediate products of the bile acids biosynthesis pathway [9]. AMACR deficiency is caused by a genetic defect, c.154T>C, which is passed down from parents to offspring in an autosomal recessive pattern.

    Epidemiology

    AMACR deficiency is a rare inborn enzymic deficiency, that has been described in the literature as few as seven times up to this day. It is usually diagnosed during adulthood, with the patients suffering from additional comorbidities, such as sensorimotor neuropathy [10] [11] [12]. A single case report has described a case of AMACR deficiency diagnosed in a neonate. The c.154T>C genetic mutation that has been found to underlie the condition has been detected in as many as 6 out of the 7 known cases.

    Sex distribution
    Age distribution

    Pathophysiology

    The process of β-oxidation that is carried out in the peroxisomes is an indispensable step in the rather complex procedure of molecular degradation. More specifically, β-oxidation contributes to the catabolism of branched fatty acids, VLCFA, polyunsaturated fatty acids and long-chain dicarboxylic acids; prostaglandins and leukotrienes are also catabolized in the peroxisomes [13]. The organelles contain various enzymes, such as two acyl-CoA oxidases, two thiolase and two bifunctional enzymes that are activated by different substrates in order to mediate β-oxidation. Thus, each type of enzyme deficiency leads to the buildup of distinct substrates.

    More specifically, the alpha-methylacyl-CoA racemase (AMACR) enzyme is the one that converts (2R)-methyl branched-chain fatty acids into (2S)-methyl branched-chain fatty acids, this conversion creates substrates that can successfully go through β-oxidation in the peroxisome. These newly formed substrates encompass pristanic acid and bile acid intermediates di- and tri hydrocholestanoic acids (DHCA and THCA) and, in the setting of an AMACR deficiency, they accumulate in excessive quantities [6].

    The presence of intermediate products of β-oxidation that are unable to complete the process cause severe symptomatology, such as late-onset cerebral ataxia, adult-onset neuropathy, white matter abnormalities, recurrent encephalopathy and epilepsy [14] [15] [16] [17]. Under some circumstances, tremor, cataract, lesions in the thalamus and pigmentary retinopathy can arise, while some individuals exhibit signs of cholestasis as early as the first days of their lives [18] [19].

    Prevention

    AMACR deficiency is a genetic condition, inherited through the autosomal recessive pattern of inheritance. Currently, there are no effective steps to prevent it.

    Summary

    α-Methylacyl-CoA racemase (AMACR) deficiency is an inborn error of the metabolic process of cholesterol. It specifically interferes with the oxidation of cholesterol's side-chain and mediates the conversion of pristanic and trihydroxycholestanoic acid into a different, stereoisomeric molecule [1] [2]. The aforementioned conversion is mandatory for the β-oxidation of the C27 bile side chain that is performed in the small cytoplasmic organelles, known as peroxisomes [3]. Thus, the absence of AMACR leads to the inability of the organism to perform the metabolic processes mentioned above and, as a result, intermediate products are released into the serum, including pristanic, di- and trihydroxycholestanoic acid [4] [5].

    AMACR deficiency is a rare disorder, which is inherited via the autosomal recessive pattern of inheritance and is otherwise referred to as congenital bile acid synthesis defect type 4 (BAS defect type 4). The genetic abnormality that leads to the disease is a mutation in the AMACR gene. Very few cases have been documented in the literature up to this day, given the rarity of AMACR; only seven patients have been officially diagnosed until now; the absence of a definite prognosis, treatment plan, even a decisive clinical presentation can be attributed to this rarity [6] [7]. In general, patients display neurological sequelae, including encephalopathy, peripheral neuropathy; cholestasis has also been observed.

    AMACR deficiency is diagnosed by a biochemical analysis of the patient's serum and urine, brain magnetic resonance imaging, a fibroblast culture and genetic tests [8]. Current treatment recommendations include the administration of cholic acid on a long-term basis and a dietary restriction of pristanic and phytanic acid intake, despite the fact that no definitive efficacy of the latter has been established.

    Patient Information

    Alpha-methylacyl-CoA racemase (AMACR) deficiency is a genetic disease. Individuals affected by it lack an enzyme which is vital for the metabolism of various substances, such as phytanic acid and pristanic acid. The body's inability to process these acids leads to their abnormally high accumulation in the patient's blood and various neurological complications.

    AMACR deficiency is not preventable. It is either inherited from the parents in an autosomal recessive way, or it is a result of a spontaneous mutation. The autosomal recessive pattern implies that the affected individual must have inherited two defective genes, one from each parent, in order for the disease to develop.

    The condition induces a variety of symptoms, which are all related to the central or peripheral nervous system and include the following:

    • Cognitive impairment: progressive loss of cognitive abilities
    • Epileptic phenomena
    • Headaches
    • Encephalopathy: inflammation of the brain
    • Stiff muscles
    • Ataxia: loss of coordinated movement
    • Damage to the peripheral nerves
    • Deteriorating vision, or congenital visual impairment, primarily due to defects of the retina

    AMACR deficiency is usually suspected when infants fail to grow, are not as active as they should be, are mentally disabled and exhibit elevated liver enzymes and an equally enlarged liver. Diagnostic tests include the detection of the presence of phytanic acid and various other metabolic products in blood that can indicate AMACR. With regard to the treatment of AMACR, patients follow a diet that has been adapted to include absolutely no phytanic and pristanic acid, even though no significant amelioration has been observed. They also receive cholic acid for long periods of time, which has been shown to stop the condition from progressing to severe stages.

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    References

    1. Bove KE, Heubi JE, Balistreri WF, Setchell KD, et al. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7:315–334.
    2. Ferdinandusse S, E. G. van Grunsven,1 W. Oostheim, et al. Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of d-bifunctional protein. Am J Hum Genet. 2002;70:1589–1593.
    3. Cuebas DA, Phillips C, Schmitz W, Conzelmann E, Novikov DK, et al. The role of alpha-methylacyl-CoA racemase in bile acid synthesis. Biochem J. 2002;363:801–807.
    4. Ferdinandusse S, Denis S, IJlst L, Dacremont G, Waterham HR, Wanders RJ, et al. Subcellular localization and physiological role of alpha-methylacyl-CoA racemase. J Lipid Res. 2000;41:1890–1896.
    5. Ferdinandusse S, Overmars H, Denis S, Waterham HR, Wanders RJ, Vreken P, et al. Plasma analysis of di- and trihydroxycholestanoic acid diastereoisomers in peroxisomal alpha-methylacyl-CoA racemase deficiency. J Lipid Res. 2001;42:137–141.
    6. Ferdinandusse S, Denis S, Clayton PT, et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Gen. 2000;24:188–891.
    7. Setchell KD, Heubi JE, Bove KE, et al. Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology. 2003;124:217–232.
    8. Van Veldhoven PP, et al. Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin K deficiency. Eur J Clin Invest. 2001;31:714–722.
    9. Van Veldhoven PP, Casteels M, Mannaerts GP, et al.Further insights into peroxisomal lipid breakdown via alpha- and beta-oxidation. Biochem Soc Trans. 2001; 29:292–298.
    10. McLean BN, Allen J, Ferdinandusee S, et al. A new defect of peroxisomal function involving pristanic acid: a case report. J Neurol Neurosurg Psychiatry. 2002; 72:396–399.
    11. Clarke CE, Alger S, Preece MA, et al.Tremor and deep white matter changes in alpha-methylacyl-CoA racemase deficiency. Neurology. 2004; 63:188–189.
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