Metabolic Crises, Recurrent, With Rhabdomyolysis, Cardiac Arrhythmias, And Neurodegeneration

A number sign (#) is used with this entry because of evidence that recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) is caused by homozygous or compound heterozygous mutation in the TANGO2 gene (616830) on chromosome 22q11.

Description

Recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) is an autosomal recessive disorder characterized by episodic metabolic degeneration affecting skeletal muscle, cardiac muscle, and the nervous system. Affected individuals usually present in childhood with acute encephalomyopathic features, including rhabdomyolysis, hypotonia, and neurologic regression, although most patients have delayed psychomotor development before the acute onset. The overall disease course is characterized by progressive neurodegeneration with epilepsy, cognitive impairment, pyramidal and cerebellar signs, and loss of expressive language. Cardiac involvement with severe arrhythmias is a consistent and potentially life-threatening manifestation (summary by Lalani et al., 2016 and Kremer et al., 2016).

Clinical Features

Lalani et al. (2016) studied 12 affected individuals from 9 families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to cardiac tachyarrhythmias. Acute rhabdomyolysis was the presentation in 10 of the 12 patients, with onset between 5 months and 8 years of age. Neurodevelopmental problems were observed in all affected individuals by early childhood, and muscle weakness, gait abnormality, or poor coordination were reported in most patients prior to the acute presentation of myoglobinuria. Seizures were present in 9 of 12 patients. The acute clinical presentation ranged from profound muscle weakness, ataxia, and/or disorientation to a comatose state, frequently precipitated by an acute illness. During these metabolic crises, hypoglycemia, hyperlactacidemia, and mild hyperammonemia were repeatedly observed. Elevated transaminases were also noted, indicative of muscle injury. Acylcarnitine profiles during acute episodes showed elevated C14:1 in at least 3 patients; another patient had elevated C10 species during the acute episode, and another showed elevated C3 (propionyl-carnitine) and C10 species. Life-threatening cardiac tachyarrhythmia presented as torsade de pointes or ventricular tachycardia in 4 (33%) of 12 patients, and intermittent prolonged QTc interval was seen in 6 (50%) of patients. The QT interval often reverted to normal between episodes, and metabolic abnormalities typically normalized outside the critical period of crises. Mitochondrial studies and muscle biopsies were essentially normal. Structural brain abnormalities, seen in 7 of 10 patients who underwent imaging, mostly reflected varying degrees of cerebral atrophy or volume loss. Gait disturbances, dysarthria, and myopathic facies were observed in most patients outside the crisis episodes. Hypothyroidism was diagnosed in 4 of 12 patients. In 1 family, affected twins from a dichorionic diamniotic pregnancy died at 2 years of age, the boy during an episode of hypoglycemia and lactic acidemia, and the girl due to worsening cardiomyopathy. In another family, 1 sib from an affected monozygotic twin pair died at 7 years of age during an acute rhabdomyolytic crisis, whereas his twin brother was alive at 11 years of age. The oldest living patient in the study cohort was 27.

Kremer et al. (2016) reported 3 unrelated individuals with recurrent encephalomyopathic crises characterized by hypoglycemia, elevated plasma creatine kinase activity, lactic acidosis, and increased acylcarnitines, as well as massive urinary excretion of lactate, ketones, and dicarboxylic acids. Prior to the first crisis, global developmental delay as well as cortical signs were observed. Although the clinical condition stabilized between episodes, the overall disease course was one of neurodegeneration, including epilepsy, cognitive impairment, pyramidal and cerebellar signs, and loss of expressive language. Optic atrophy and sensorineural hearing impairment were each seen in 1 patient. Cardiac involvement, with severe arrhythmias including torsade de pointes and long QT syndrome, was a consistent and potentially life-threatening condition. Increased TSH levels indicating hypothyroidism were documented in all 3 patients.

Molecular Genetics

Lalani et al. (2016) performed whole-exome sequencing in 12 patients from 9 families with recurrent metabolic encephalomyopathic crises associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, who were negative for mutation in rhabdomyolysis-associated genes. A recurrent homozygous missense mutation in the TANGO2 gene (G154R; 616830.0001) was identified in 4 unrelated Hispanic probands, and homozygous deletion of exons 3-9 (616830.0002) was identified in 4 probands from 2 families of European origin. In addition, the proband from a mixed Hispanic/European family was compound heterozygous for G154R and the exon 3-9 deletion. In another Hispanic family, the proband was homozygous for a splice site mutation (616830.0003), and 2 affected sibs from a Saudi Arabian family carried a homozygous deletion of exons 4-6 (616830.0004). The mutations segregated fully with disease in the families, and none of the variants was present in homozygosity in control databases.

Kremer et al. (2016) performed whole-exome sequencing in 3 unrelated individuals with recurrent metabolic encephalomyopathic crises associated with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, and identified homozygosity or compound heterozygosity for mutations in the TANGO2 gene in all 3 patients: 1 patient was homozygous for deletion of exons 3-9, another was compound heterozygous for the exon 3-9 deletion and a 1-bp deletion (616830.0005), and the third patient was homozygous for a nonsense mutation (R140X; 616830.0006). The mutations segregated with disease in each of the families, and none of the variants had been reported in homozygous state in public databases.