hypotonia

This mitochondrial DNA depletion syndrome allows normal development in the first year of life.  By 10-18 months of age, muscle weakness and coordination become evident.  Deep tendon reflexes are diminished or absent.  The muscle deficits are relentlessly progressive and by teenage years most individuals are wheelchair-bound.  Generalized seizures are common.  Facial and limb dyskinesia of an athetoid nature is evident to a variable degree.  A sensory polyneuropathy develops in many patients.  Cerebellar atrophy is evident on neuroimaging.

Neurosensory hearing loss may become evident late in the first decade of life.  The amount of hearing loss is progressive, leading eventually to profound deafness.  Some patients experience a complete loss of vestibular caloric responses. 

Most individuals live to adulthood but a severe form of this disease in which liver damage and encephalopathy occur limits the lifespan to about 5 years.

The phenotype is variable, likely depending upon the size of the deletion.  Cardiovascular disease, primarily hypertension and large vessel stenosis, are among the most important features.  The elastin arteriopathy lead to thickened arterial walls with peripheral pulmonary stenosis and supravalvular aortic stenosis.  The facies is considered unique with bitemporal narrowing, a wide mouth, full lips, malocclusion, small jaw, and prominent earlobes.  The teeth are small and widely spaced.  Connective tissue abnormalities include joint hyperextensibility, hernias, lax skin, hypotonia, and bowel/bladder diverticulae.  Small birth size is common and infants often fail to thrive but at puberty patients can experience a growth spurt.  Ultimate height in adults is usually in the third centile.

Vocal cord anomalies and paralysis can result in a hoarse voice.  A sensorineural hearing loss is common among adults but hyperacusis is often present in young children.

Hypercalcemia and hypercalciuria are common and some (10%) have hypothyroidism.

Most individuals have some cognition difficulties and delays but normal intelligence has also been reported.  Patient personalities consist of anxiety, attention deficit disorder, marked friendliness and a high level of empathy.  Visiospatial construction is often impaired.  Most adults are unable to live independently.

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

The clinical diagnosis of Canavan disease is suggested when the triad of hypotonia, macrocephaly and head lag is present.  It is a progressive form of spongy degeneration of the central nervous system but its onset, course, and severity are variable.

The disease is often evident before 6 months of age and survival is limited to a few months or years in infants with such early onset.  Such patients have the most severe and rapidly progressive disease.  It is noteworthy that, even though such infants do not achieve normal milestones such as sitting and standing, they do often interact socially by laughing, smiling, and reaching for objects.  Most young children are quiet and apathetic but some become irritable and develop spasticity as they grow.  CNS damage is evident as leukodystrophy on neuroimaging studies but this may not be present in later onset, milder forms of the disease.         

Other individuals may have a later and milder juvenile onset of symptoms and may present with delayed speech or motor development late in the first decade.  They often attend regular school but may benefit from tutoring and speech therapy.  They may live to adolescence or early adulthood.  Maldevelopment of the organ of Corti is responsible for hearing deficits in some children.

The small number of reported patients has limited description of the full phenotype but this seems to be a generalized neurological disorder.  Patients have been reported with global developmental delay, hypotonia, cognitive delays, ataxia/clumsiness, and speech difficulties.  Neuroimaging may reveal abnormalities in various brain stuctures including the cerebellum, cerebrum, vermis, and corpus callosum in 40% of patients.       

Infants may appear normal at birth but within a few months develop signs of developmental stagnation with onset of tonic-clonic seizures.  Irritability, poor feeding, vomiting and failure to thrive are important features.  Generalized hypotonia is evident but lower limb deep tendon reflexes may be present.  Normal developmental milestones are never achieved and patients are unresponsive to their environment.  Older individuals develop non-purposeful choreothetoid movements.  The EEG shows multifocal epileptiform discharges and brain MRIs show diffuse atrophy in older patients.

Hypo- and hyperpigmented skin macules in a 'salt and pepper' pattern, have been described.  These vary from 2-5 mm in size and are located primarily on the extremities.  These are found among children older than 3 years of age and some parents have reported that the hyperpigmentation may decrease after many years.  No such lesions were found in mucosal tissue.        

This is a disorder of glycosylation important to the formation of glycoproteins and glycolipids.  Neurological signs such as tremor, clonus, and muscle fasiculations may be seen soon after birth.  Other neurological abnormalities eventually include psychomotor retardation, seizures, mental retardation, hyperexcitabilty, and ataxia.  Failure to thrive and feeding difficulties are evident early.  Progressive microcephaly is a feature.  Liver dysfunction can lead to coagulopathy and hypoproteinemia with hepatomegaly is sometimes present.  Some patients have facial anomalies, inverted nipples, and subcutaneous fat pads.  The MRI may show areas of brain atrophy, ischemia, and focal necrosis.

Longevity is limited with 2 of 3 reported patients dying within 2 years of life.