Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant.

Acute necrotizing encephalopathy (ANE) is clinically characterized by fever, acute alteration of consciousness, seizures, and rapid progression to coma within days of onset of a viral illness occurring in healthy children without evidence of central nervous system infection. Brain magnetic resonance imaging (MRI) shows multiple symmetrical lesions affecting primarily the thalami but also brain stem, putamina, periventricular white matter, and cerebellum. Most cases of ANE are sporadic and nonrecurrent. However, a missense variant in RANBP2 has been identified in some families with recurrent ANE (OMIM # 608033), also named autosomal dominant ANE (ADANE). Clinical manifestation, clinical course, and brain MRI imaging findings of six affected members of two distinct families with ADANE were described. Sequencing revealed heterozygous c.1754C > T variant in RANBP2 (p.Thr585Met) in affected and asymptomatic family members. Only few ADANE families have been reported and it is the first description in South America. Differential diagnosis of Leigh disease and acute disseminated encephalomyelitis is discussed. Our report reinforces incomplete penetrance of ADANE and intrafamilial phenotypic variability of outcome.

Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency is a severe neonatal mitochondrial myopathy that resolves spontaneously. It is caused by the homoplasmic m.14674T>C mtDNA mutation and additional nuclear variants in genes interacting with mt-tRNAGlu have been detected in some patients. We present detailed clinical, imaging, and muscle biopsy findings in a boy and a girl with neonatal hypotonia, feeding difficulties, lactic acidosis, and ragged red fibers. Both patients show fat replacement on muscle imaging, which was mild in the boy, but severe in the girl, affecting mostly the posterior leg muscles. In addition to the homoplasmic m.14674T>C, both patients carried heterozygous variants in QRSL1 (c. 686T>G; p.Val299Gly) and EARS2 (c.358C>T; p.Arg120Trp), respectively. It is very important to recognize the clinical and morphological signs of reversible infantile respiratory chain deficiency as patients should receive intensive supportive care in the first 6 months of life. Understanding the mechanism of the spontaneous recovery may lead to novel therapeutic perspectives in other mitochondrial diseases.

Early-onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion.

Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction-ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large-scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A-related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation.

Homozygosity enhances severity in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3, or Machado-Joseph disease, is an autosomal dominant neurodegenerative disease characterized by a wide spectrum of clinical findings that include progressive cerebellar ataxia. All affected individuals have an expanded CAG repeat mutation in one allele of the ATXN3 gene. An inverse relationship exists between the age of onset and the number of repeats in the abnormal expanded allele. The case described is that of a child with Machado-Joseph disease, daughter of a consanguineous affected couple. She inherited the expanded allele in homozygosity with CAG repeat size similar to that of her parents, and had a distinct early onset (4 years of age) and severe clinical phenotype. This case supports the conclusion that homozygosity aggravates the clinical phenotype. Loss of function of the normal expressed ataxin-3, or possibly aggregation of ataxin-3, may be implicated in disease mechanism.