Type I 3-Methylglutaconic Aciduria (MGCA1) is a metabolic disorder inherited in an autosomal recessive manner. It is caused by a deficiency in the 3-methylglutaconyl-CoA hydratase encoded by the AUH gene, leading to abnormal excretion of urinary organic acids. While the pediatric phenotype encompasses a spectrum ranging from isolated developmental delay to severe forms with leukodystrophy, developmental delay, spastic tetraplegia and movement disorders, the adult phenotype corresponds to a leukodystrophy with spastic ataxia, progressive dementia, and optic neuropathy. Due to its rarity, MGCA1 is most likely underdiagnosed, or diagnosed with an important delay, leading to inadequate care or genetic counselling. A better understanding of the disease's phenotype is thus required to facilitate its clinical and genetic diagnosis, in turn favoring clinical care and genetic counselling. We report two new MGCA1 patients, including an adult male patient with pure, late-onset, and progressive cerebellar ataxia, without optic neuropathy or leukodystrophy. A young female patient case is also reported with moderate developmental delay and leukodystrophy, offering 14-year follow-up data under carnitine supplementation. In both cases, urinary organic acid chromatography was critical to the diagnostic process by demonstrating abnormal and specific urinary organic acids excretion. The description of new, mild and/or late-onset phenotypes expands the clinical and radiological spectrum of MGCA1. Our results show that late-onset MGCA1 patients may present with pure cerebellar ataxia without leukodystrophy, contrasting with current knowledge. These results support the fact that AUH should always be sequenced in patients with pure cerebellar ataxia, but also that urinary organic acid chromatography being a simple, rapid, and cost-effective test, should be performed as a first-tier analysis in all patients with unresolved neurological symptoms. The importance of identifying MGCA1 patients is reinforced by the possibility of implementing a low-risk and possibly effective therapy with low-protein diet and L-carnitine supplementation.

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. 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. 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. 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. Barth syndrome is a multisystem disorder characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, and prepubertal growth delay; however, not all features may be present in an affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with bacterial infections and aphthous ulcers, pneumonia, and sepsis. Skeletal myopathy predominantly affects the proximal muscles, and results in delays in development of early motor skills. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies. The diagnosis of Barth syndrome is established in a male proband with suggestive findings and either an increased monolysocardiolipin-to-cardiolipin ratio (if available) or a hemizygous pathogenic variant in TAFAZZIN (formerly TAZ) identified by molecular genetic testing. The diagnosis of Barth syndrome is usually established in a female proband with suggestive clinical findings and a heterozygous TAFAZZIN pathogenic variant identified by molecular genetic testing. Targeted therapy: Elamipretide is indicated for the improvement of muscle strength in individuals with Barth syndrome. Treatment of manifestations: Standard treatment of cardiac issues include: (1) for cardiac arrhythmia, consideration of antiarrhythmic medications or implantable cardiac defibrillator (ICD); (2) for heart failure, careful fluid and volume management and avoidance of overdiuresis and dehydration, standard heart failure medications, and cardiac transplantation when heart failure is severe and intractable. Interventions for other findings include granulocyte colony-stimulating factor for neutropenia; physical therapy for skeletal muscle weakness; standard treatment for talipes equinovarus and/or scoliosis; feeding therapy and consideration of gastrostomy tube placement for persistent feeding issues; uncooked cornstarch prior to bedtime for hypoglycemia; standard management of developmental delay / intellectual disability. Prevention of secondary complications: Aspirin therapy to prevent clot formation in those with severe cardiac dysfunction and/or marked left ventricular noncompaction; antibiotic prophylaxis to prevent recurrent infections; limit fasting or provide intravenous glucose infusion prior to planned medical procedures; regularly monitor blood potassium concentrations during administration of IV fluids that contain potassium and during episodes of diarrhea; consult with nutritionist and/or gastroenterologist to determine optimal caloric delivery. Surveillance: Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires at least annual electrocardiography with Holter monitor and echocardiography; as-needed electrophysiologic studies to assess for potentially serious cardiac arrhythmia; at least semiannual complete blood count with differential as well as with all febrile episodes; at each visit, measurement of height and weight, clinical assessment of strength, and clinical assessment for scoliosis; every three to five years during childhood, formal assessments of developmental progress and educational needs. Agents/circumstances to avoid: Prolonged fasting, use of rectal thermometers in those with neutropenia, and use of succinylcholine. Although growth hormone is typically not indicated as most affected males will attain normal stature by adulthood, recommendations about use of human growth hormone may vary based on endocrinology testing and recommendations. The muscular involvement in Barth syndrome may increase the risk for malignant hyperthermia compared to the general population. Evaluations of relatives at risk: Molecular genetic testing (if the TAFAZZIN pathogenic variant in the family is known) or monolysocardiolipin-to-cardiolipin ratio testing (if the TAFAZZIN pathogenic variant in the family is not known) of male sibs of a proband and male relatives in the maternal lineage is appropriate to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Barth syndrome is inherited in an X-linked manner. If the mother of the proband has a TAFAZZIN pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females typically do not manifest the disease. Affected males transmit the TAFAZZIN pathogenic variant to all of their daughters and none of their sons. If the TAFAZZIN pathogenic variant has been identified in an affected family member, identification of female heterozygotes and prenatal/preimplantation genetic testing for Barth syndrome are possible.

MEGDEL syndrome is a rare autosomal recessive disease characterized by 3-methylglutaconic aciduria, deafness-dystonia, hepatopathy, encephalopathy, and leigh-like syndrome, which results from biallelic pathogenic variants in SERAC1 gene. The diagnosis is commonly challenging due to the diverse clinical manifestations. Herein, we report the first case of MEGDEL syndrome from the Egyptian population. This is a 7-year-old boy born to first cousins Arab parents from Egypt with family history of unexplained deaths of 3 siblings during the neonatal period. He presented with developmental regression since the age of 2 years resulting in marked muscle weakness with no head support, generalized spasticity more prominent in lower limbs, and aphonia, but intact hearing. The child had excessive urinary excretion of 3-methylglutaconic acid, and his brain magnetic resonance imaging showed characteristic basal ganglia affection with "Putaminal eye sign." Whole-exome sequencing demonstrated a likely pathogenic homozygous c.1404-2A>G variant in SERAC1 gene. This report expands the epidemiological and phenotypic spectrum of MEGDEL syndrome by reporting the first case from the Egyptian population who had relatively delayed onset and no evident hepatopathy or deafness.

3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.

The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood DNAJC19 gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.