Neuroectodermal melanolysosomal disease (ORPHA:33445)
A rare genetic neurological disease characterized by silvery hair, profound dysfunction of central nervous system, abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblast and other cells.
Epidemiology
Fewer than 20 cases have been reported worldwide; the prevalence is less than 1/1 000 000 worldwide.
Clinical description
Presentation is in neonates with silver-leaden hair of the scalp, eyebrows and eyelashes, and a silvery sheen present over the body hair. Over time, sun-exposed skin becomes hyperpigmented with a bronze color with generalized hypopigmentation of covered skin. Neurological dysfunction presents either in early infancy or in childhood, manifesting with seizures, severe hypotonia and intellectual disability, and typically progressing to either flaccid or spastic hemiplegia, quadriplegia and ataxia. Individuals with childhood onset initially have normal psychomotor development but subsequently suffer sudden severe neurological regression, including loss of speech, mobility, the ability to feed ones-self, and typically remain bed-ridden. Affected individuals have a wide spectrum of ocular abnormalities including mild vascular sheathing with features of papilledema, nystagmus, diplopia, amaurosis, and absence of pupillary reflex. Brain imaging may show abnormalities including cerebellar and cortical atrophy.
Etiology
The disease is associated with MYO5A mutations. The hyperpigmentation results from defective transfer of melanin from melanocytes to keratinocytes. Neurological abnormalities are linked to impaired function of a molecule playing a common role in melanocytic and neuronal organelle function.
Diagnostic methods
Diagnosis requires light microscopic examination of skin and hair shafts, immunological and peripheral blood smear evaluation. Skin biopsy shows irregular distribution and size of melanin granules in the basal layer, and inclusion bodies in fibroblasts. Hair shafts demonstrate large melanin clumps irregularly distributed along the shaft. Additional laboratory analysis should exclude immunological impairment, abnormal giant intracytoplasmic granules in neutrophils and connective tissue disease.
Differential diagnosis
The disease appears to be related or allelic to Griscelli syndrome type 1. Two other silvery hair syndromes, Griscelli syndrome type 2 and Chédiak-Higashi syndrome, are excluded due to lack of accelerated phase and presence of immunological impairment.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Familial cases indicate that the pattern of inheritance is autosomal recessive, with a sibling recurrence risk of 25%.
Management and treatment
Management and treatment are symptomatic. Steroids, anticonvulsants and antipyretics have been used without success. Seizures have been reported to show improvement in one patient with ACTH therapy.
Prognosis
The disease typically results with death in childhood due neurological complications; the oldest patient reported was 12 years old and had achieved some developmental milestones.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Dr Lokesh LINGAPPA  - Dr Prithuja PODYAL