We report on a patient with a severe, rare neonatal form of non-dystrophic myotonia. The patient presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness leading to severe hypoxia and loss of consciousness. Muscle biopsy was non-specific and electromyography revealed intense generalized myotonia. The myotonic episodes improved after introducing oral mexiletine and maintaining room temperature at 28 degrees C. The patient died at 20 months of age following a bronchopulmonary infection. A previously undescribed de novo heterozygous c.3891C > A change, which predicts p.N1297K in the SCN4A gene. Mutations within the voltage-gated sodium channel alpha-subunit gene (SCN4A) have been described in association with several phenotypes including paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis, and potassium-aggravated myotonias. The cold-sensitive episodes of stiffness followed by weakness suggested the diagnosis of channelopathy in our patient. However, her neonatal onset, the triggering of severe episodes by exposure to modest decreases in temperature, involvement of respiratory muscles with prolonged apnea, early-onset muscle hypertrophy, psychomotor retardation, and fatal outcome are evocative of a distinct clinical subtype. Our observation expands the phenotypic spectrum of sodium channelopathies.
Alpha‐mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi‐systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha‐mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha‐mannosidase in leucocytes and screening for abnormal urinary excretion of mannose‐rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDER) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3–23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two‐sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.
Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable.
Synopsis
Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
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