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SGPL1 encodes sphingosine-1-phosphate lyase, the final enzyme of sphingolipid metabolism. In 2017, a condition featuring steroid-resistant nephrotic syndrome and/or adrenal insufficiency associated with pathogenic SGPL1 variants was reported. In addition to the main features of the disease, patients often exhibit a range of neurologic deficits. In a handful of cases, brain imaging results were described. However, high-quality imaging results and a systematic analysis of brain MR imaging findings associated with the condition are lacking. In this study, MR images from 4 new patients and additional published case reports were reviewed by a pediatric neuroradiologist. Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis and prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions. MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations., (© 2020 by American Journal of Neuroradiology.)

Background: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations., Methods: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms., Results: We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene., Conclusions: PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature., Competing Interests: All authors state that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.

3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: l-2-Hydroxyglutaric aciduria is a rare progressive neurometabolic disorder of childhood inherited as an autosomal recessive trait. Urine organic-acid screening is necessary for its diagnosis. Although it is a disorder of childhood, recently adult cases have been reported., Cases: Here we report 4 adult patients in whom diagnoses were established in adulthood. These patients had some interesting features. First, their diagnoses were delayed until adulthood because of mild clinical symptoms. In such cases, the typical MRI findings are the best diagnostic clue for l-2-Hydroxyglutaric aciduria. Second, there was a correlation between the severity of the clinical course and the extent of MRI findings. The cerebral white-matter lesions were diffuse and confluent on the MRI of 3 of the 4 patients, who also experienced a rapidly progressive clinical decline. Third, there were different clinical presentations even within the same family., Conclusions: For the evaluation of patients with symptoms referable to cerebellar, pyramidal, extrapyramidal, or cognitive impairment as well as seizures associated with subcortical white-matter and symmetrical dentate nuclei and basal ganglia involvement on MRI, urine organic acid analysis should be included in the evaluation, regardless of patient's age.

Objective: To study the clinico-investigative profile and outcome of patients with inborn errors of metabolism (IEM) presenting to the pediatric intensive care unit (PICU)., Methods: Records of all patients admitted in tertiary care centre PICU between August 2007 and September 2008 with a diagnosis of IEM were retrieved the details of clinical presentation, laboratory results, treatment and outcome were noted and analysed., Results: Eleven (2.6%) out of 420 PICU admissions during the study period had a diagnosis of IEM with a high mortality rate of 36%. Clinical presentation was quite varied., Conclusion: IEM are not uncommon in PICU. Simple biochemical tests and neuroimaging findings provide vital clues to the diagnosis of IEM.

Methylmalonic acidemia caused by an l-methylmalonyl-CoA mutase deficiency. The mut(0) type is associated with significant mortality and morbidity, but tandem mass spectrometry has made early detection possible. Five patients were identified through newborn screening for elevated propionylcarnitine (C3-carnitine) levels. These patients received a positive screening result at a median age of 10 days (range, 5-18 days). When treated at a median age of 11 days (range, 3-50 days), 2 patients were asymptomatic, and only one was significantly acidotic (pH <7.2), but all had various degrees of hyperammonemia (range, 127-1,244 mumol/L). Magnetic resonance imaging of the brain was performed in 4 patients shortly after diagnosis, and the results were all abnormal. Four patients were followed. There was no further metabolic decompensation after the initial episodes, but their mean developmental quotient was only 50. These results suggest that early hyperammonemia can lead to significant brain damage in methylmalonic acidemia. Therefore, treatment of this disease in newborns must be more aggressive.

Myelination starts in the latter half of gestation. It is initiated by oligodendrocyte progenitor cells. Three sequential steps can be distinguished: (1) initial ensheathment of axons by premyelin sheaths generated by oligodendrocyte progenitor cells; (2) initial insertion of myelin basic protein (MBP) into transitional sheaths; and (3) generation of mature MBP-rich myelin. Different inborn errors of metabolism can interfere with different stages of these physiological processes, causing white-matter diseases, i.e. toxic leukoencephalopathies. Some inborn errors of metabolism disturb the formation of myelin by being toxic to oligodendrocytes or by interference with the biosynthesis of cholesterol and lipids, e.g. globoid cell leukodystrophy and phenylketonuria. Remethylation defects, e.g. methylenetetrahydrofolate reductase deficiency, cobalamin C, D, E, F and G defects, interfere with the expression, processing and insertion of MBP. The concept of excitotoxicity, which has been developed in neurons, has recently been modified and has been extended to the oligodendroglial lineage. Mitochondriopathies and cerebral organic acid disorders may cause secondary excitotoxicity resulting in toxic encephalopathies, which may affect both neurons and oligodendrocytes. This review aims to present relevant diseases, summarizing recent knowledge on mechanisms and formulating testable hypotheses of pathophysiology leading to new and improved treatment strategies.

Magnetic resonance imaging of a girl with giant axonal neuropathy revealed a progressive white matter disease. In close agreement with histopathological features reported previously, localized proton magnetic resonance spectroscopy at 9 and 12 years of age indicated a specific damage or loss of axons (reduced N-acetylaspartate and N-acetylaspartylglutamate) accompanied by acute demyelination (elevated choline-containing compounds, myo-inositol, and lactate) in white matter as well as a generalized proliferation of glial cells (elevated choline-containing compounds and myo-inositol) in both gray and white matter.

We report a five-year-old boy with 4-hydroxybutyric aciduria. The child presented with global developmental delay, severe hypotonia and myoclonic seizures. The urine 4-hydroxybutyric acid was 1038 times that of normal, and other organic acids related to its further metabolism were also increased. Electroencephalography showed findings indicative of cerebral dysfunction. However, other neurophysiological studies were normal. Clinical improvement was observed after the administration of vigabatrin and dextromethorphan. Magnetic resonance imaging of the brain revealed cerebellar vermin atrophy and subtle white matter changes in the cerebral hemispheres. Fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomographic (FDG PET) scan of the brain showed a marked decrease in the cerebellar metabolism, probably related to atrophy of cerebellar vermis and secondary cerebellar deafferentation. FDG PET scan is found to be of value in the understanding and assessment of brain functional alterations. It may be useful in monitoring and optimizing treatment strategies of this rare disease.

Cobalamin C (cblC) defects result in decreased activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), with subsequent methylmalonic acid-uria and homocystinuria. Patients typically show failure to thrive, developmental delay and megaloblastic anaemia. Vitamin B12 therapy has been beneficial in some cases. We report a now 4-year-old Hispanic girl with cblC disease documented by complementation analysis, with progressive neurological deterioration and worsening head MRI changes while on intramuscular hydroxocobalamin begun at age 3 weeks. Oral carnitine and folic acid were added at age 1 year. Blood levels of methylmalonic acid were reduced to treatment ranges. In the absence of acute metabolic crises, she developed microcephaly, progressive hypotonia and decreased interactiveness. Funduscopic examination was normal at age 13 months. At age 19 months, she developed nystagmus, and darkly pigmented fundi and sclerotic retinal vessels were observed on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed diffuse white-matter loss with secondary third and lateral ventricle enlargement, a thin corpus callosum, and normal basal ganglia. At age 15 months, progression of the white-matter loss, as well as hyperintense globi pallidi, were present. Interval progression of both grey- and white-matter loss was seen at age 27 months. We therefore caution that progressive neurological deterioration and head MRI abnormalities may still occur in cblC disease, despite early initiation of hydroxocobalamin therapy and improvement in toxic metabolite concentrations in physiological fluids.

Aceruloplasminemia is a disorder of iron metabolism characterized by degeneration of the retina and basal ganglia. CSF from affected patients showed a threefold increased iron concentration that was associated with increased superoxide dismutase activity and lipid peroxidation products. These findings support the hypothesis that iron-mediated lipid peroxidation contributes to neurodegeneration in patients with aceruloplasminemia. Such measurements may have value in assessing disease progression as well as the results of iron chelation and other therapeutic interventions.

The majority of patients with mitochondrial disease have significant neuropathology, with the most common features being spongiform degeneration, neuronal loss and gliosis. Although there is considerable overlap between different mitochondrial diseases, the nature and distribution of the lesions is sufficiently distinctive in some cases to suggest a specific diagnosis. On the other hand, a number of different defects in cerebral energy metabolism are associated with common patterns of neuropathology (e.g. Leigh syndrome), suggesting that there is a limited range of responses to this type of metabolic disturbance. There are many descriptions of neuropathological changes in patients with mitochondrial disease, but there has been remarkably little investigation of the underlying pathogenic mechanisms. Comparisons with other conditions of cerebral energy deprivation such as ischaemia/hypoxia and hypoglycaemia suggest a possible role for excitotoxicity initiated by excitatory amino acid neurotransmitters. An additional contributing factor may be peroxynitrite, which is formed from nitric oxide and the oxygen free radicals which accumulate with defects of the mitochondrial electron transport chain. Mitochondrial diseases are often characterized by episodes of neurological dysfunction precipitated by intercurrent illness. Depending on the severity of the metabolic abnormality, each of these episodes carries a risk of further neuronal death and the result is usually progressive accumulation of irreversible damage. The balance between reversible functional impairment and neuronal death during episodes of metabolic imbalance is determined by the effectiveness of various protective mechanisms which may act to limit the damage. These include protective metabolic shielding of neurons by astrocytes and suppression of electrical activity (and hence energy demands) by activation of ATP-gated ion channels. In addition, recent evidence suggests that lactic acid, the biochemical abnormality common to these conditions, may not be toxic at moderately high concentrations but may in fact be protective by reducing the sensitivity of neurons to excitotoxic mechanisms.

Glutaric acidemia type II is associated with neonatal hypoketotic hypoglycemia, metabolic acidosis, profound hypotonia, progressive cardiomyopathy, and early death. Deficiency of either electron transfer flavoprotein or electron transport flavoprotein:ubiquinone oxidoreductase leads to intramitochondrial accumulation of metabolites of compounds oxidized by enzymes that transfer electrons to flavoprotein. No detailed results of antemortem neuroimaging or magnetic resonance spectroscopy have been described previously. We investigated a patient with typical neonatal onset glutaric acidemia type II without obvious dysmorphogenesis or renal malformations. Cranial tomographic scan revealed hypoplastic temporal lobes and marked widening of the sylvian fissures ("bat-wing" appearance). Cranial magnetic resonance imaging documented underdeveloped frontal and temporal lobes with delayed myelination and hypoplasia of the corpus callosum. 31P-Magnetic resonance spectroscopy of muscle was grossly abnormal with a very low energy state consistent with mitochondrial dysfunction. 1H-Magnetic resonance spectroscopy of brain revealed elevated intracerebral lactate concentration and abnormally high choline/creatine ratio suggestive of dysmyelination. These findings constitute the first in vivo evidence of a developmental encephalomyopathy in glutaric acidemia type II.

The results of CT and/or MRI of the brain in 107 patients with different types of organic acidemia are presented. The CSF spaces were wide in more than two-thirds of the patients, in 46 slightly-to-moderately and in 26 markedly-to-severely dilated. Marked widening of the operculae was found in all 5 patients with glutaric acidemia type 1, but open opercula was also found in other organic acidemias. White matter changes were found in about half the patients, in 28 mildly-to-moderately pronounced, in another 28 marked or severe. Basal ganglia or central pathway pathology was seen in a total of 34 patients, i.e. 32%. These changes in 25 patients involved the caudate and/or lentiform nuclei: in 14 cases the T2 signal was increased and volume loss was present, in 9 cases increased T2 signal with preserved volume was found (in one of these the changes were transient). In 2 patients, both with ethylmalonic aciduria (cause unknown), only small high T2 spots were seen in the caudate heads and the putamina. In 4 patients, all suffering from methylmalonic acidemia, only the globus pallidus was affected. In 3 patients, all with beta-ketothiolase deficiency, high T2 intensity changes were seen only in the postero-lateral putamina. The remaining 8 patients represent a variety of different locations of lesions. The CT or MRI findings in many patients with organic acidemias should alert the radiologist that a neurometabolic disorder may be present; in some cases the location and appearance of the lesions may even suggest the correct diagnosis.

Congenital ornithine transcarbamylase (OTC) deficiency in humans is associated with seizures and mental retardation. As part of a series of studies to delineate the neurochemical features of OTC deficiency, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively, were measured in brain regions of the congenitally hyperammonemic sparse-fur (spf) mouse, a mutant with an X-linked inherited defect of OTC. ChAT activities were reduced by 63% (P < 0.01) in cerebral cortex of spf mice compared with CD-1/Y controls. Activities of the GABA nerve terminal marker enzyme, glutamic acid decarboxylase, on the other hand, were within normal limits. Using an immunohistochemical technique with a monoclonal antibody to ChAT, a significant loss of ChAT-positive neurons was observed throughout the cerebral cortex, septal area and diagonal band of spf mice. These results suggest that a loss of forebrain cholinergic neurons is a feature of congenital OTC deficiency in these mutants. Possible pathogenetic mechanisms responsible for the cholinergic neuronal loss in congenital OTC deficiency include neurotoxic effects of ammonia and accumulation of quinolinic acid.

Morphologic appearance and metabolic disturbances of the brain of a patient with L-2-hydroxyglutaric acidemia were investigated with use of magnetic resonance imaging and localized proton magnetic resonance spectroscopy in vivo. Whereas magnetic resonance imaging revealed increased internal and external cerebrospinal fluid spaces as well as patchy white matter lesions, metabolic deviations included a 50% decrease of N-acetylaspartate (neuronal marker), a 75% increase of myo-inositol (glial marker), and a 40% decrease of choline-containing compounds in white matter relative to age-matched controls. A clinical deterioration of the patient was clearly reflected in a follow-up examination 22 mo later, resulting in a further reduction of N-acetylaspartate and a more pronounced enhancement of myo-inositol. No elevation of lactate was observed. The magnetic resonance spectroscopy findings are in line with a generalized neurodegenerative process in L-2-hydroxyglutaric acidemia but also suggest a defect in phosphatidyl inositol metabolism of glial cells.

We report clinical and neuropathological studies of 2 patients with glutaric aciduria type 1. A 10-month-old male with involuntary movements expired suddenly at home. The second, a 15-year-old female, died after three episodes of acute encephalopathy including a Reye syndrome-like episode and an episode of severe hypoglycemia. Hypocarnitinemia was also present. Selective involvement of type II muscle fibers was observed during the Reye syndrome-like episode. Magnetic resonance imaging of the 2 patients showed marked widening of the sylvian fissure, atrophy of the basal ganglia, and white matter lesions. Neuropathology of the 10-month-old patient showed: (1) temporal and frontal lobe hypoplasia, (2) degeneration of the putamen and the pallidum, (3) mild status spongiosus in the cerebral white matters, (4) heterotopic neurons in the cerebellum, and (5) hypoplasia of the cerebral white matter. This patient appeared to manifest a migration and/or maturation abnormality of the brain as well as previously observed basal ganglia and white matter degeneration.

The investigation of the brain from a seven-day-old girl who died from a disorder in the metabolism of methylmalonic acid revealed a severe reactive gliosis of the cerebral white matter and the deeper layers of the cortex, incomplete development of the fetal granular layer of the cerebellum and the Bergmann glial cells, and delayed myelination of the cerebellum, the brainstem, and the cervical spinal cord. We suggest that some of the described neuropathological findings are an immediate consequence of a disturbed methylmalonic acid metabolism starting in utero, and not exclusively a secondary phenomenon due to accumulation of metabolites and acidosis postpartum.

Intraperitoneal injections of cupric chloride prevent neuronal degeneration in the hemizygous brindled mottle mouse, MO br/Y, a murine model of kinky hair syndrome (KHS) in humans. At 6-9 months after two i.p. injections, the brain of MO br/Y revealed slightly increased amounts of lipofuscin pigments in the cerebral cortical neurons, cytoplasmic inclusions in the thalamic neurons, and axonal spheroid formation in the tuber cinereum, cerebellum and brain stem. Increased numbers of mitoses, bizarre hyperchromatic giant nuclei, and numerous clear vacuoles were frequently seen in the proximal renal tubular epithelium. Numerous myelin figures were conspicuous features in these epithelial cells at ultrastructural level. Such changes were not found in the littermate controls but in the heterozygous brindled mottled mouse, MO br/ +, identical changes were noted in equal or even higher frequency. These observations suggest that cupric chloride injections effectively modify the expression of the genetic defect in MO br/ Y.

A 12-year-old girl had chronic nonspherocytic hemolytic anemia due to triosephosphate isomerase deficiency. Developmental and motor delay and muscular weakness were followed by cerebellar dysfunction and finally spasticity with hyperreflexia. Abnormal histopathological findings were hyaline cell bodies and axonal "spheroids" in the hypothalamus and cerebellar cortex, severe neuronal loss in the dentate and olivary nuclei, and partial loss of cerebellar Purkinje's and granular layer cells (olivocerebellar atrophy).

Two infants with the cerebro-hepato-renal syndrome (Zellweger's disease) exhibited cholestasis and progressive liver damage. Because abnormalities of mitochondrial structure and function have been reported in this condition, we examined the bile acids for evidence of defects in the mitochondrial phase of bile acid synthesis, namely, oxidation of the cholesterol side chain to form C-24 bile acids. The presence of increased amounts of the C-27 bile acid intermediates (trihydroxycoprostanic acid, varanic acid, and dihydroxycoprostanic acid) were noted and identified by gas-liquid chromatography-mass spectrosocopy confirming that a defect in the mitochondrial pathways for bile acid side chain cleavage is involved in this entity. The clinical course, liver histopathology, and hepatocyte ultrastructural abnormalities suggest that these bile acids may reflect an underlying mitochondrial dysfunction in this disease and possibly may contribute to the progressive hepatic lobular fibrosis observed in these patients.

Pipecolic acid is a cyclic secondary imino acid produced in the metabolism of lysine. The metabolic role and fate of pipecolic acid in the human central nervous system are largely unknown. The biochemical defect in two brothers, both less than two years of age, with minor dysmorphic features, progressive neurological dysfunction, and hepatomegaly was identified as hyperpipecolatemia. At autopsy, the older brother's brain weight was increased, with bilateral pallor of the putamen. Distinctive changes included accumulation of 1-1.5 micrometer periodic acid-Schiff (PAS) positive, diastase-resistant, Alcian blue-negative, non-lipid, non-fluorescent granules in astrocytes, satellite cells, and perivascular foot processes. Both light and electron microscopy showed total absence of these granules in neurons. In the older sibling, the liver showed micronodular cirrhosis with distinctive intrahepatocytic accumulation of 0.2-1 micrometer membrane-bound material of low electron density. Pericellular fibrosis and similar cytoplasmic inclusions were present in the liver biopsy from his brother. The distinctive astrocytic storage phenomenon and the liver changes are compared to the findings in Zellweger's syndrome and lysinuric protein intolerance, which are also associated with altered pipecolate metabolism.

A morphological survey of the central nervous system of a NCTR-Balb/C mouse afflicted by neurovisceral storage disease was performed. It has been demonstrated that this mutant is characterized by primary dysmyelination, which is evident as early as 12 days of age. The failure of myelin formation in the CNS was shown by histochemical and ultrastructural methods. Inasmuch as neither lipid-containing macrophages nor infiltrating mononuclear cells were apparent, secondary demyelination could be excluded. The multiform ultrastructural appearance of the storage material in the various CNS cell types suggested heterogeneity of the accumulated substances. The storage materials which reacted positively with periodate-Schiff reagent, but not with other histochemical stains, are most likely the accumulated gangliosides and neutral glycosphingolipids identified previously in this mutant's brain. Considering the probable role of cholesterol ester in the early phases of myelinogenesis, in conjunction with the fact that the NCTR-Balb/C mouse carries a defect in the esterification of exogenously derived cholesterol, it is possible that the later metabolite is relevant to the impaired myelin formation.

The clinical and pathologic features of a male patient with generalized glutathione deficiency and pyroglutamic aciduria are presented. The patient died at the age of 28 years. He was mentally retarded from infancy and developed progressive tremor, retardation of movement, and ataxia as from the age of 16. Neuropathologic examination of the brain disclosed a selective atrophy of the granule cell layer of the cerebellum and focal lesions in the visual cortex and the thalamus. The type and distribution of the lesions resembled those seen after mercury intoxication. However, in our patient the damage was probably caused by the lack of protection of glutathione against oxidative damage in the brain. Possible treatment of this rare metabolic disorder might include external supply of an antioxidant, e.g., a thiol capable of penetrating the blood brain barrier.