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A group of heterogeneous muscle diseases are caused by dystrophin gene (DMD) mutations. We hereby present a male patient with a diagnosis of symptomatic dilated cardiomyopathy at 44 years-old who developed, soon after, weakness of distal right upper limb. At the age of 58, neurological examination revealed severe atrophy of right thenar muscles, flexion contractures on the right elbow, wrist and fingers, bilateral calf hypertrophy, myotatic areflexia in the upper limbs and hyporeflexia in the lower limbs. Manual muscle examination showed distal weakness of right upper limb muscles, severe on abductor pollicis brevis and extensor pollicis longus, and milder on interossei, finger extensors and brachioradialis muscles. Further testing revealed CK of 1500 U/L, a myopathic pattern on electromyography, and myopathic changes on right deltoid muscle biopsy, with immunohistochemistry showing focal sub-expression of dystrophin. Cardiac workup revealed a severe reduction in left ventricular ejection fraction, with a left ventricle of increased dimensions and global hypo-contractibility. A next-generation sequencing based panel for muscular diseases was performed and a nonsense mutation (c.C7525T) was identified in exon 51 of DMD gene, present in 70% of the gene readings (consistent with mosaicism).

SIGMAR1 gene encodes a non-opioid endoplasmic reticulum (ER) protein which is involved in a large diversity of cell functions and is expressed ubiquitously in both central and peripheral nervous systems. Alterations of its normal function may contribute to two different phenotypes: juvenile amyotrophic lateral sclerosis (ALS 16) and distal hereditary motor neuropathies (dHMN). We present the case of a female patient, of 37-years-old, with distal muscle weakness and atrophy beginning in childhood and slowly progressive in the first two decades of life. Neurological examination revealed a symmetrical severe muscle wasting and weakness in distal lower and upper limbs, with claw hands, footdrop with equinovarus deformity and hammer toes, generalized areflexia and normal sensory examination. The electrodiagnostic study revealed a pure chronic motor peripheral nerve involvement without signs of demyelination. The molecular study found the deletion c.561_576del on exon 4 and a deletion of all exon 4, in the SIGMAR1 gene. info:eu-repo/semantics/publishedVersion

Mutations in the GRIN2A gene, which encodes the GluN2A (glutamate [NMDA] receptor subunit epsilon-1) subunit of the N-methyl-d-aspartate receptor, have been identified in patients with epilepsy-aphasia spectrum disorders, idiopathic focal epilepsies with centrotemporal spikes, and epileptic encephalopathies with severe developmental delay. However, thus far, mutations in this gene have not been associated with a nonepileptic neurodevelopmental disorder with dystonia.The objective of this study was to identify the disease-causing gene in 2 siblings with neurodevelopmental and movement disorders with no epileptiform abnormalities.The study method was targeted next-generation sequencing panel for neuropediatric disorders and subsequent electrophysiological studies.The 2 siblings carry a novel missense mutation in the GRIN2A gene (p.Ala643Asp) that was not detected in genomic DNA isolated from blood cells of their parents, suggesting that the mutation is the consequence of germinal mosaicism in 1 progenitor. In functional studies, the GluN2A-A643D mutation increased the potency of the agonists L-glutamate and glycine and decreased the potency of endogenous negative modulators, including protons, magnesium and zinc but reduced agonist-evoked peak current response in mammalian cells, suggesting that this mutation has a mixed effect on N-methyl-d-aspartate receptor function.De novo GRIN2A mutations can give rise to a neurodevelopmental and movement disorder without epilepsy. © 2018 International Parkinson and Movement Disorder Society.

Clinical and basal biochemical characteristics of each patient with hyperphenylalaninemia. (DOCX 48 kb)

Mutations in the GRIN2A gene, which encodes the GluN2A (glutamate [NMDA] receptor subunit epsilon-1) subunit of the N-methyl-d-aspartate receptor, have been identified in patients with epilepsy-aphasia spectrum disorders, idiopathic focal epilepsies with centrotemporal spikes, and epileptic encephalopathies with severe developmental delay. However, thus far, mutations in this gene have not been associated with a nonepileptic neurodevelopmental disorder with dystonia.

Clinical and biochemical characteristics of healthy controls. (DOCX 21 kb)

Characteristics of Hyperphenylalaninaemia patients with altered values of the biochemical parameters studied. (DOCX 85 kb)

Background: Mitochondrial diseases due to deficiencies in the mitochondrial oxidative phosphorylation system (OXPHOS) can be associated with nuclear genes involved in mitochondrial translation, causing heterogeneous early onset and often fatal phenotypes. Case report: The authors describe the clinical features and diagnostic workup of an infant who presented with an early onset severe encephalopathy, spastic-dystonic tetraparesis, failure to thrive, seizures and persistent lactic acidemia. Brain imaging revealed thinning of the corpus callosum and diffuse alteration of white matter signal. Genetic investigation confirmed two novel mutations in the GFM1 gene, encoding the mitochondrial translation elongation factor G1 (mtEFG1), resulting in combined deficiencies of OXPHOS. Discussion: The patient shares multiple clinical, laboratory and radiological similarities with the 11 reported patients with mutations involving this gene, but presents with a stable clinical course without metabolic decompensations, rather than a rapidly progressive fatal course. Defects in GFM1 gene confer high susceptibility to neurologic or hepatic dysfunction and this is, to the best of our knowledge, the first described patient who has survived beyond early childhood. Reporting of such cases is essential so as to delineate the key clinical and neuroradiological features of this disease and provide a more comprehensive view of its prognosis.