developmental delay

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.       

A wide variety of systemic anomalies have been reported.  Congenital heart defects (primarily septal) and CNS malformations are among the most common features, reported in 85% and 55% respectively.  Tetralogy of Fallot is considered by some to be the most common heart malformation.  Growth and mental retardation are found in nearly 100%.  The pinnae are often set low and hearing loss is common.  Ear anomalies, both internal and external, have been described in 91%, and some degree of conduction and/or sensorineural deafness is present in 62%.  Choanal atresia is found in at least 57% of patients.  This along with cleft palate and sometimes esophageal atresia or reflux often contributes to feeding difficulties which are common in all age groups.  Cranial nerve deficits are seen in 92% of patients and more than one nerve is involved in nearly 3 of 4 patients.  The most common cranial nerve defects involve numbers IX, X, VIII, and V.  Facial palsies are an especially important feature. Hypogonadotropic hypogonadism and underdevelopment of the external genitalia are often seen, especially in males.  One-third of patients have limb anomalies and many have short digits.  The facies is considered by some as characteristic with a square configuration, broad forehead, flat midface, and a broad nasal bridge.

Infant and childhood morbidity is high with feeding difficulties a major cause of death.

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.

Slow somatic growth and neural development are usually noted in the first few years of life.  Young children may acquire some independence and motor skills but progressive neurologic deterioration is relentless with loss of milestones and eventual development of mental retardation or dementia.  Patients often appear small and cachectic, with a 'progeroid' appearance.  The hair is thin and dry, and the skin is UV-sensitive but the risk of skin cancer is not increased.  Sensorineural hearing loss and dental caries are common.  Skeletal features include microcephaly, kyphosis, flexion contractures of the joints, large hands and feet, and disproportionately long arms and legs.  Perivascular calcium deposits are often seen, particularly in various brain structures while the brain is small with diffuse atrophy and patchy demyelination of white matter.  Peripheral neuropathy is characterized by slow conduction velocities.  Poor thermal regulation is often a feature. 

Type A is considered the classic form of CS.  Neurological deterioration and atherosclerotic disease usually lead to death early in the 2^nd decade of life but some patients have lived into their 20s.  

The onset of systemic symptoms such as unsteadiness occurs some time in the second decade of life.  Irritability, delayed development, and psychomotor retardation may be evident in children whereas older individuals can have frank dementia.  The MRI may reveal cerebral and cerebellar atrophy.  Seizures may have their onset by the third decade.  Numbness, tingling and pain in the extremities are common.  EMG and nerve conduction studies can demonstrate a peripheral neuropathy.  Neurogenic muscle weakness can be marked and muscle biopsy may show partial denervation. Some patients have hearing loss.  A few patients have cardiac conduction defects. 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present.