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Microphthalmia and microcornea are seen in most individuals and one patient had unilateral clinical anophthalmia. Hyperopia and cataracts may be present. Nystagmus is common. One patient had a corneal opacity. The chorioretinopathy has not been described beyond evidence of the maculopathy, attenuated retinal vessels, and occasionally hyperpigmented zones. The ERG is either not recordable or consistent with a severe rod-cone dystrophy. Vitreous inclusions and a ‘vitreoretinal dystrophy’ with falciform retinal folds were noted in several patients. A traction detachment was present in one and bilateral serous detachments were noted in another.
Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays. Profound intellectual disability is a consistent feature. Physical growth is retarded and patients have shortness of stature. Most patients are unable to sit, stand, or walk unassisted. One patient died at 5.5 years of age while another was alive at 20 years of age. Rare patients may have hearing loss and seizures.
Scoliosis, kyphosis, and lordosis may be seen while other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.
The forehead slopes markedly. Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small. Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.
Homozygous mutations in the PLK4 gene (4q28.2) segregate with this condition. Its product localizes to centrioles and plays a central role in centriole duplication.
No treatment is know.
Ocular findings like systemic features are highly variable both within and between families. Vision can be normal but in other patients it is severely reduced to the range of 20/200. The pupils may respond sluggishly or even paradoxically to light. ERG recordings have been reported to be normal in some patients, but absent or reduced in others. The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy. Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas. The eyebrows are often highly arched.
The oculomotor system is frequently involved. Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements. Compensatory head thrusting is often observed. A pendular nystagmus may be present while esophoria or esotropia is present in many patients.
There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias. Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features. Hyperactivity and aggressiveness combined with dependency require constant vigilance and care. Postaxial polydactyly is a feature of some cases. Hypotonia is evident at birth. Liver failure and renal disease develop in many individuals. Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the ‘molar tooth sign’ in the isthmus region considered to be a diagnostic sign. The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.
The facies features are said to be distinctive in older individuals. The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.
This is a clinically and genetically heterogeneous group of disorders with many overlapping features. Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern. Mutations in at least 18 genes have been identified. One, OFD1 (300804), is located on the X chromosome (Xp22.2).
Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.
Ocular examinations in 4 adult individuals of a single family aged 18 to 27 years were reported to have optic atrophy. One of these had a horizontal nystagmus and another was described as having a vertical nystagmus. No ocular evaluations were available for 2 children, aged 2 and 6 years. Visual acuity testing was not reported but all individuals participated appropriately in family and educational activities.
This is a congenital disorder with cerebral ataxia (limb and truncal), spastic paraparesis (increased lower limb tone with brisk knee jerks and extensor plantar responses), cerebellar and spastic dysarthria, learning difficulties and emotional lability as prominent features. The onset of both speech and mobility are delayed. Older individuals have slow and spastic tongue movements with brisk jaw jerks, and increased tone in the upper limbs. Motor function progressively declines although even older individuals in the third decade of life remain mobile albeit with an increasingly spastic and ataxic gait, and require only minimal assistance with self-care. Children in grade school require special education accommodations but there is no obvious deterioration in intellectual function as they mature.
This is an autosomal recessive disorder resulting from homozygous mutations in the MTPAP gene (10p11.22). The mutation leads to a defect of mitochondrial mRNA maturation in which the poly(A) tails are severely truncated.
Optic atrophy is also present in some patients who have autosomal dominant spastic ataxia with miosis (SPAX7) (108650) and in another form of autosomal recessive childhood-onset spastic ataxia and mental retardation (270500).
No treatment is known but special education and physical and speech therapy may be helpful.
Leber congenital amaurosis is a collective term applied to multiple recessively inherited conditions with early-onset retinal dystrophy causing infantile or early childhood blindness. There are no established diagnostic criteria. First signs are usually noted before the age of 6 months. These consist of a severe reduction in vision accompanied by nystagmus, abnormal pupillary responses, and photophobia. Ametropia in the form of hyperopia is common. Keratoconus (and keratoglobus) is frequently found in older children but it is uncertain if this is a primary abnormality or secondary to eye rubbing as the latter is commonly observed. Repeated pressure on the eye may also be responsible for the relative enophthalmos often seen in these patients. The ERG is reduced or absent early and permanently. Final visual acuity is seldom better than 20/400 and perhaps one-third of affected individuals have no light perception. Some individuals experience a period of vision improvement.
The retina usually has pigmentary changes but these are not diagnostic. Retinal vessels are generally attenuated. The RPE may have a finely granulated appearance or, in some cases, whitish dots, and even ‘bone spicules’.
A variety of metabolic and physical abnormalities have been reported with LCA but many publications are from the pre-genomic era and the significance of such associations remains uncertain. Most extraocular signs result from delays in mental development but it is uncertain what role, if any, that visual deprivation plays. Perhaps 20% of patients are mentally retarded or have significant cognitive deficits.
Leber congenital amaurosis is genetically heterogeneous with 17 known gene mutations associated with the phenotype. It is also clinically heterogeneous both within and among families and this is the major obstacle to the delineation of individual clinicogenetic entities. As more patients are genotyped, it is likely that more precise genotype-phenotype correlations will emerge. At the present time, however, it is not possible to use clinical findings alone to distinguish individual conditions.
Below are links to the genotypic and phenotypic features of the 17 known types of LCA. All cause disease in the homozygous or compound heterozygous state.
LCA type OMIM# Locus Gene Symbol
It is likely that more mutant genes will be identified since these are found in only about half of patients studied in large series.
*(Heterozygous mutations in CRX may also cause a cone-rod dystrophy).
Until recently, no treatment was available for LCA. However, results from early clinical trials with adeno-associated virus vector mediated gene therapy for RPE65 mutations in LCA 2 show promise. Subretinal placement of recombinant adeno-virus carrying RPE65 complementary DNA results in both subjective and objective improvements in visual function. Patients generally report subjective improvement in light sensitivity and visual mobility. Some recovery of rod and cone photoreceptor function has been documented. Studies have also documented an improvement in visual acuity, size of visual field, pupillary responses, and in the amouunt of nystagmus. More than 230 patients have now been treated and improvements seem to be maintained for at least 3 or more years. However, we have also learned that along with the enzymatic dysfunction of RPE65 that disrupts the visual cycle, there is also degeneration of photoreceptors which continues after treatment and the long term prognosis remains guarded. Multiple phase I clinical trials have demonstrated the safety of this approach and phase III trials are now underway.
It is crucial for patients to be enrolled early in sensory stimulation programs to ensure optimum neural development. For patients with residual vision, low vision aids can be beneficial. Vocational and occupational therapy should be considered for appropriate patients.
Subtle cherry red spots have been reported in one patient. More than half (53%) have abnormal VEP response but the ERG is normal. Optic atrophy with blindness is not uncommon but the full ocular phenotype remains unknown. A 6-month-old male child had MRI T2 evidence of intracranial optic nerve hypertrophy which was attributed to an accumulation of globoid cells.
There is considerable variation in the time of onset and rate of progression in Krabbe disease, even within families. Patients with infantile disease may present with symptoms at about 6 months of life, while others are not diagnosed until late childhood or adolescence. Some evidence of psychomotor retardation is often the first sign of disease with ataxia and limb spasticity soon following. Irritability is an early sign. Neurophysiologic studies often show abnormal nerve conduction and this has been documented even in newborns. The disorder is one of progressive neurodegeneration of both central and peripheral nervous systems leading to weakness, seizures and loss of protective reflexes. The MRI may reveal T2 hyperintensity in cerebral and cerebellar white matter, internal capsules and pyramidal tracts. Infection and respiratory failure are responsible for most deaths.
The life-span of Infants with Krabbe disease is approximately one year while those with late-onset disease may not develop symptoms until almost any age and the clinical course is highly variable.
This is an autosomal recessive disorder secondary to mutations in the GALC gene (14q31) encoding the enzyme galactosylceramidase, important in the growth and maintenance of myelin.
One patient has been reported with ‘atypical’ Krabbe disease (611722) secondary to a homozygous mutation in the PSAP gene (10q22.1). The infant had a deficiency of saposin A as well as decreased galactocerebrosidase activity in white blood cells
Normal blood galactocerebrosidase can be restored and CNS deterioration may be delayed or improved with transplantation of allogeneic hematopoietic stem cells or umbilical cord blood. However, some patients have residual language deficits and mild to severe delays in motor function. Results are better if treatment is commenced during infancy before development of symptoms. These treatments are experimental and long range outcomes remain uncertain.