メチルグルタコン酸尿症

A 7-month-old spayed female mixed-breed dog was evaluated for a subacute, progressive, cerebellar syndrome characterized by ataxia and intention tremors. Brain magnetic resonance imaging (MRI) revealed moderate cerebellar atrophy and mild bilateral symmetrical intra-axial lesions at the level of the caudate nuclei. A neurodegenerative disorder was suspected. Over a 2-year period, signs of neurologic disease worsened with suspected myoclonic epileptic seizures and severe cerebellar ataxia. Follow-up MRI showed progressive cerebellar and cerebral atrophy, as well as well-defined, bilateral, and symmetrical lesions affecting the caudate nuclei. Histopathology revealed severe cerebellar degeneration with a loss of Purkinje cells and depletion of the granular and molecular layers. Malacic areas at the level of the caudate nuclei characterized by extensive necrosis were observed. Genetic testing identified a clear top candidate variant in the SERAC1 gene on chromosome 1. These findings are consistent with multiple system degeneration, a rare inherited neurodegenerative disorder resembling MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome) in humans.

BACKGROUND: Barth syndrome is an X-linked disorder characterised by cardiomyopathy, growth abnormalities, neutropenia, and 3-methylglutaconic aciduria. It is caused by pathogenic variants in TAFAZZIN, which encodes a mitochondrial protein essential for cardiolipin remodelling. In this study, we describe the case of a patient with Barth syndrome in whom initial research genetic testing missed a 5' untranslated region deletion in TAFAZZIN that was later identified through a phenotype-guided reanalysis of exome sequencing data. CASE PRESENTATION: A male infant presented with dilated cardiomyopathy at 7 months of age and underwent cardiac transplantation at 19 months. Initial comprehensive cardiac genetic testing was indeterminate. Subsequent clinical investigations recorded a slight increase in the levels of 3-methylglutaconic acid and intermittent neutropenia, and a history of intermittent neutropenia was noted in his mother and maternal grandmother, prompting a consideration of Barth syndrome. A reanalysis of exome sequencing data identified a hemizygous 116 base pair deletion spanning the 5' untranslated region and start codon of TAFAZZIN. An RNA analysis from the proband's cardiac tissue amplified truncated TAFAZZIN transcripts, and Western blotting confirmed the complete loss of full-length protein, consistent with the loss of the start codon and failure of translation initiation from a downstream in-frame methionine. CONCLUSION: We report a novel 116 bp TAFAZZIN deletion that prevents protein expression due to the loss of the canonical start codon. This case highlights the importance of including non-coding regions in genetic analysis and the diagnostic value of phenotype-guided reanalysis of genetic test data.

Pathogenic variants in SPG7 cause autosomal dominant progressive muscular atrophy. SPG7 encodes an inner mitochondrial membrane protein, paraplegin. Burgeoning lines of evidence have continued to suggest important roles for paraplegin in mitochondria function. Here we report elevated levels of biochemical markers of mitochondria dysfunction [3-methylglutaconic acid and 3-methylglutaric acid (in urine and blood) as well as plasma Growth Differentiation Factor 15 (GDF 15)] in a 65-year-old woman with a heterozygous pathogenic SPG7 variant [c.1529C > T (p.Ala510Val)], and evidence of muscle disease as well as chronic cerebral vasculopathy.

BACKGROUND: CLPB-related mitochondrial disease causes congenital neutropenia, developmental delay/intellectual disability, progressive brain atrophy, movement disorders, cataracts, and 3-methylglutaconic aciduria. Both monoallelic and biallelic forms exist. This retrospective cohort study compared clinical outcomes and genotype-structure-phenotype correlations across zygosity groups. METHODS: Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey. In silico modeling assessed structural impact. A modified CLPB Disease Burden Index (DBI) quantified severity. RESULTS: Median age at last follow-up was 4.0 years (IQR: 0.25-12.6) in biallelic and 12.0 years (IQR: 5.3-21.0) in monoallelic cases. Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%). Stop/stop genotypes were associated with greater disease burden than missense combinations. Structural predictions-particularly variants causing nonsense-mediated decay or ankyrin domain disruption-were stronger survival predictors than zygosity or age of onset. Early-onset disease (<12 months) correlated with more severe progression. Later onset often resulted in milder phenotypes. Hematologic and neurologic features overlapped across zygosity; cataracts and dystonia were more common in biallelic cases. Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time. Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes. Granulocyte colony-stimulating factor was associated with improved survival. CONCLUSIONS: This is the largest cohort study to date comparing biallelic and monoallelic CLPB deficiency. Structural variant impact-particularly ankyrin domain disruption-emerged as a key prognostic factor.