メチルグルタコン酸尿症

INTRODUCTION: Type VIII 3-methylglutaconic aciduria (MGCA8) is a neurodegenerative disorder which involves biallelic pathogenic variants of HTRA2. This gene encodes a mitochondrial serine protease responsible for apoptosis regulation and mitochondrial proteins' quality. Clinical manifestations include dysfunctional muscle tone, movement disorder, severe encephalopathy, epileptic seizures, dysautonomia, feeding difficulty, intermittent neutropenia, bradycardia, and recurrent apneas, often progressing into respiratory failure. CASE REPORT: We describe a newborn presenting with abnormal muscle tone, progressive dystonic movements, recurrent apneas, feeding difficulties, and epileptic seizures. Biochemical analysis revealed a markedly elevated urinary 3-methylglutaconic acid, and genetic test identified biallelic pathogenic variant in HTRA2. Brain MRI revealed progressive brain atrophy, thalamic hypoplasia, and ventriculomegaly. EEG recordings found organizational abnormalities that turned into epileptic spasms. Despite intensive care, the patient suffered rapid neurological decline and died following a prolonged apnea episode. Thereafter the family had another infant diagnosed with the same biallelic pathogenic variant in HTRA2, that died a few days after birth due to respiratory failure. DISCUSSION: MGCA8 is a lethal condition characterized by loss-of-function biallelic mutations in HTRA2, which lead to mitochondrial dysfunction and altered apoptosis regulation, especially in the brain. High levels of 3-methylglutaconic acid in urine are one important early diagnostic marker, when associated with a consistent clinical phenotype. Our report contributes to the limited existing case series and provides a detailed characterization of the EEG findings associated with this rare condition.

The evolving field of fetal neurology can offer insights into early nervous system development through antenatal dynamic ultrasonography and maternal perception of movements. The spectrum of abnormal fetal movements ranges from fetal akinesia, often associated with arthrogryposis multiplex congenita (AMC), to increased repetitive movements, typically indicating fetal seizures. Nonepileptic hyperkinetic movement disorders of the fetus are rarely documented. Here, we report a female infant who had clonus-like movements in utero and postnatally. Antenatal ultrasonography revealed polyhydramnios, fetal growth restriction, and repetitive clonus-like movements (∼5 Hz), which the mother perceived as frequently "shaking" her. The infant required resuscitation and intubation at delivery. AMC, ectrodactyly, cataract, axial hypotonia, and absent primitive reflexes were noted, along with persistent high-frequency, low-amplitude clonus-like movements without accompanying ictal epileptic activity on the EEG. Laboratory findings included markedly elevated serum creatine kinase levels attributed to sustained contractions, severe neutropenia, and 3-methylglutaconic aciduria. Despite supportive care, she died of respiratory failure on day 15. Whole-exome sequencing established the diagnosis as caseinolytic peptidase B deficiency, an autosomal recessive primary mitochondrial disorder caused by pathogenic variants in the nuclear-encoded CLPB gene. This is a unique case of AMC, paradoxically occurring with hyperkinesia rather than with global hypokinesia, but the hyperkinetic movement repertoire is limited and restrictive. This case underlines the diagnostic value of integrating antenatal history and imaging with detailed postnatal phenotyping by a multidisciplinary team in neurometabolic disorders.

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.