Severe congenital X-linked myopathy with excessive autophagy secondary to an apparently synonymous but pathogenic novel variant.

X-linked myopathy with excessive autophagy is a rare inherited disease characterized by aberrant accumulation of autophagic vacuoles in skeletal muscle. Affected males usually show a slow progression and the heart is characteristically spared. We present four male patients from the same family with an extremely aggressive form of this disease, requiring permanent mechanical ventilation from birth. Ambulation was never achieved. Three died, one in the first hour of life, one at 7 years and one at 17 years, the last death being a consequence of heart failure. Muscle biopsy showed pathognomonic features of the disease in the 4 affected males. Genetic study found a novel synonymous variant in VMA21, c.294C>T (Gly98=). Genotyping was consistent with co-segregation with the phenotype in an X-linked recessive manner. An alteration of the normal splice pattern was confirmed by transcriptome analysis, proving that the apparently synonymous variant was the cause of this extremely severe phenotype.

Lessons learned from a sporadic FUSopathy in a young man: a case report.

BACKGROUND: In frontotemporal dementia (FTD) spectrum, younger patients may correspond to fusopathy cases, and cognitive decline could be rapidly progressive. We present a clinical and neuropathological description of a patient. CASE PRESENTATION: A 37-year-old man, without a family history of neurodegenerative diseases, was brought by his family to consult for dysarthria and behavioural change. Initial exploration showed spastic dysarthria and disinhibition. He progressively worsened with a pseudobulbar syndrome, right-lateralized pyramidal signs, left hemispheric corticobasal syndrome and, finally, lower motor neuron signs in his right arm. He died four years after the initiation of the syndrome from bronchopneumonia. Laboratory tests (including blood and cerebrospinal fluid (CSF)) were normal. Magnetic resonance imaging (MRI) and fluorodeoxyglucose-containing positron emission tomography (PET-18F-FDG) showed left fronto-insular atrophy and hypometabolism. Subsequently, 123I-ioflupane (DaT-SCAN®) single-photon emission computed tomography (SPECT) was pathologic, manifesting bilaterally decreased activity with greater affection on the left side. Only a third electromyogram (EMG) detected denervation in the last year of evolution. No mutations were found in genes such as Tau, progranulin, C9orf72, FUS, TDP-43, CHMP2B, or VCP. In necropsy, severe frontotemporal atrophy with basophilic neuronal cytoplasmic and intranuclear inclusions, negative for tau and TAR DNA binding protein 43 (TDP-43), but positive for fused in sarcoma (FUS) consistent with specifically basophilic inclusions body disease (BIBD) type was found. CONCLUSIONS: In patients affected by FTD, particularly the youngest, with rapidly progressive decline and early motor affection, fusopathy must be suspected. These cases can include motor signs described in the FTD spectrum. Lower motor neuron affection in EMG could be detected late.

Central nervous system involvement in adult-onset relapsing hemophagocytic lymphohistiocytosis responsive to maintenance treatment with anakinra.

A 43 year-old male presented with a relapsing and progressive systemic inflammatory disorder with central nervous system (CNS) involvement. After a two years follow up, he was diagnosed with hemophagocytic lymphohistiocytosis (HLH), based on clinical, laboratory and radiological findings. Treatment was started with anakinra, a recombinant humanised interleukin-1 (IL-1) receptor antagonist. Clinical response was good. Laboratory and radiological findings showed no disease activity throughout a five years follow-up period. Several immunosuppressive agents have been used in HLH without any good outcomes. This is the first case report of HLH with CNS involvement responsive to chronic treatment with anakinra.

A novel dominant mutation in CRYAB gene leading to a severe phenotype with childhood onset.

BACKGROUND: αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance. METHODS: The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques. RESULTS: CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization. CONCLUSIONS: The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.

Secondary coenzyme Q10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders.

We evaluated the coenzyme Q10 (CoQ) levels in patients who were diagnosed with mitochondrial oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders (n=72). Data from the 72 cases in this study revealed that 44.4% of patients showed low CoQ concentrations in either their skeletal muscle or skin fibroblasts. Our findings suggest that secondary CoQ deficiency is a common finding in OXPHOS and non-OXPHOS disorders. We hypothesize that cases of CoQ deficiency associated with OXPHOS defects could be an adaptive mechanism to maintain a balanced OXPHOS, although the mechanisms explaining these deficiencies and the pathophysiological role of secondary CoQ deficiency deserves further investigation.

Phenotypic variability in a Spanish family with a Caveolin-3 mutation.

UNLABELLED: We report a Spanish family affected from a late onset, hand-involved and autosomal dominant distal myopathy associated to Caveolin-3 mutation. Signs of muscle hyperexcitability and hyperckemia were observed in the youngest relatives but not motor symptoms. PATIENTS AND METHODS: Neurological examination was performed in all members of the family. Muscle biopsy sample was taken from the proband and DNA genomics was amplified for the two exons of Cav-3 by the polymerase chain reaction (PCR) in all the affected members and in three asymptomatic relatives. RESULTS: Signs of muscle hyperexcitability and hyperckemia were observed in the affected members from early ages. Cav-3 expression was greatly reduced in the sarcolemma of the proband's muscle. Genetic studies revealed a G --> A transition at nucleotide position 80 in exon 1 of the Cav-3 gene (c.80G>A), generating a Arg --> Gln change at codon 27 (p.R27Q) of the amino acid chain in heterozygous state, while no mutation was found in unaffected members. CONCLUSIONS: Signs of muscle hyperexcitability and hyperckemia at early ages may predict the development of a late onset autosomal dominant hand-involved myopathy associated to Cav-3 mutation in the family reported herein.