Congenital Cataract-Hypertrophic Cardiomyopathy-Mitochondrial Myopathy Syndrome

Congenital cataract - hypertrophic cardiomyopathy - mitochrondrial myopathy (CCM) is a mitochondrial disease (see this term) characterized by cataracts, hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise.

Epidemiology

Prevalence of CCM is unknown; approximately 40 cases have been reported to date in disparate locations throughout the world.

Clinical description

Clinical features include congenital cataract (total or rapidly progressive), hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise. CCM may present in two forms, a neonatal lethal form or a chronic form. Hypertrophic cardiomyopathy is diagnosed at birth in half of the patients in both forms. Approximately half of the patients die within the first year of life due to cardiac failure. Nystagmus, strabismus, hypotonia, hyporeflexia and delayed motor development are occasional features. Marked lactic acidemia occurs with even limited muscular exertion. Patients who survive neonatal period and infancy, manifest the chronic form with stable cardiomyopathy and myopathy and have a normal intellect. Physical mobility is impaired due to muscular weakness in most patients.

Etiology

In the majority of CCM patients mutations (nonsense, frame-shift, start codon or splice site) in the AGK gene have been identified. The AGK gene encodes the mitochondrial acylglycerol kinase which plays a role in the assembly of adenine nucleotide translocator (ANT), an essential component of the oxidative phosphorylation in mitochondria. Two patients with distinct autosomal recessive SLC25A4 mutations have been reported (one of whom had cardiomyopathy but not cataract). The SLC25A4 gene encodes the heart and muscle specific isoform 1 of the mitochondrial ANT. The etiology remains genetically unsolved in the rest of cases of CCM. The milder affected individuals carried either splice site or start codon mutations.

Diagnostic methods

Diagnostic procedures include serum and urine analysis for lactic acid, radiology and echocardiogram for findings of cardiomyopathy. Muscle biopsy from cardiac and skeletal muscle reveals storage of lipid and glycogen, mitochondrial abnormalities, ANT deficiency and mild decrease of respiratory chain complexes I and IV. Genetic testing may reveal autosomal recessive mutations in AGK and SLC25A4 and it should be considered early in diagnostic workup.

Differential diagnosis

Differential diagnoses include mitochondrial encephalo-cardio-myopathy due to TMEM70 deficiency, isolated ATP synthase deficiency and Barth syndrome (see these terms).

Antenatal diagnosis

Prenatal genetic testing may be possible for families with affected children.

Genetic counseling

The reported mutations are transmitted in an autosomal recessive manner.

Management and treatment

CCM patients require cataract surgery during infancy and medical management of cardiomyopathy with standard therapy. Patients may require palliative care and a wheelchair for locomotion.

Prognosis

Approximately half of the reported patients die in the first year of life due to cardiac failure. The longest surviving patients are in their fifth decade of life.