NeurometPlus

Incidence

AR disease. This form is the most frequent form of disease, representing 60 to 70 % of all cases. The incidence has been estimated in one over 40,000 births.The gene for ASA is located in chromosome 22.

Clinical Characteristics

The condition starts insidiously in the second year of life. Occasionally, the onset may be abrupt following an infection. Early development usually proceeds normal and most children will have been found to walk but some have some delay. 15 % do not walk independently. The first symptoms usually start between 14 and 16 months of age with progressive difficulties in walking. The lower limbs become weak with general recurvatim and frequent falling. If the child is not walking yet, he looses the ability to stand without support. The clinical symptoms may vary from patient to patient. It may present as a flaccid paraparesis with hypotonia, absent tendon reflexes and no Babinski behaving as a polyneuropathy which may last several months until a year or so later, when pyramidal signs appear. More frequently, a combination of pyramidal signs like spasticity and bilateral Babinski is observed with depressed deep tendon reflexes. Another rare presentation is a spastic paraplegia with hyperactive reflexes. In all the three clinical presentations, there is evidence of peripheral nerve involvement with marked slowing of nerve conduction velocity motor and sensory. EMG is usually normal. Nerve conduction velocity may be reduced before symptoms appear. Initially, mental status is normal without visual problems. Non paralytic squint may occur sometimes with pendular nystagmus. Spinal fluid protein is high and early finding. It may exceed 100 mg. %. Occasionally, mild elevation of gammaglobulin may occur for unknown reason. MRI reveals a hyperintensity in the periventricular and central white matter on T2 imaging. There is no enhancement after gadollinium. The white matter changes tend to start in the occipital parietal region periventricularly. After six to eighteen months of the beginning of the condition, the child becomes unable to stand and then to sit up. Poor head control and axial hypotonia is evident. Upper limbs become spastic and weak and may develop intention tremors in the arms. Dysarthria, drooling and dysphagia then appear. DTRs may be hyper or hypoactive. Most of the times are depressed. Flaccid movements of limbs may be painful. Later, vision gets worse and optic atrophy is present in one third of patients. Seizures occur in a small proportion and never are a prominent manifestation. EEG abnormalities are late and non-characteristic. Head size is usually normal. Sulfatides accumulate in kidneys without impairing its function. Gallbladder fails to fill in cholecystograms as a result of sulfatide deposition in the mucosa. As the condition advance, the child becomes decerebrate or decorticated and his posture may have intermittent tonic spasms and present pseudobulbar signs and muscle wasting. That usually occurs between three and seven years of age. Diagnosis can be made by thin layer chromatography of the urinary sediment, which reveals marked increase in sulfatide level in all patients. The enzyme determination of arylsulfatase A (ASA) is performed in leukocytes and cultured fibroblasts. Occasionally, arylsulfatase A is normal in very affected patients probably due to deficiency of activator protein SAP1 which can be confirmed by tests using specific antibodies. Molecular analysis of DNA is now essential to confirm diagnosis and evaluating family screening in prenatal diagnosis. Occasionally, sural nerve biopsy or conjuntival biopsy detects pathognomonic deposits of sulfatide in Schwann cells and macrophages. Occasionally levels of ASA can be very low in asymptomatic individuals without the condition and they have no evidence of sulfatiduria nor metachromatic deposits in peripheral nerves. This state has been termed ASA pseudodeficiency. The condition is inherited as autosomal recessive. Heterozygotes have 50 % levels of normals. Pathologically, sulfatide accumulates in oligodendrocytes and macrophages in white matter where demyelination occur. Sulfatides may be found in kidney and gallbladder, in hepatocytes, Kupffer cells and epithelium of biliary ducts. Sulfatide deposits have a brownish or reddish color (metachromasia) when frozen sections are stained by cresyl violet or toluidine blue, contrasting with the blue cell nuclei of fibroblasts in Schwann cells. Electron microscopy localizes sulfatides to lysosomes, having a lamellar structure which frequently assumes a prismatic pattern. There is no effective treatment. Bone marrow transplantation if done early may slow or halt the progression of the disease but long term follow up is needed to evaluate the apparent benefits. If lesions in the CNS are already well developed, the risk of the procedure probably are higher than its potential benefits.The gene for ASA is located in chromosome 22 and the gene for protein activator SAP1 is in chromosome 10.

Precipitants

no

Provocation Tests

no

Diagnostic Procedures

EB-W, EB-F. DB. Diagnosis can be made by thin layer chromatography of the urinary sediment, which reveals marked increase in sulfatide level in all patients. The enzyme determination of arylsulfatase A (ASA) is performed in leukocytes and cultured fibroblasts. Occasionally, arylsulfatase A is normal in very affected patients probably due to deficiency of activator protein SAP1 which can be confirmed by tests using specific antibodies. Molecular analysis of DNA is now essential to confirm diagnosis and evaluating family screening in prenatal diagnosis. Occasionally, sural nerve biopsy or conjuntival biopsy detects pathognomonic deposits of sulfatide in Schwann cells and macrophages. Occasionally levels of ASA can be very low in asymptomatic individuals without the condition and they have no evidence of sulfatiduria nor metachromatic deposits in peripheral nerves. This state has been termed ASA pseudodeficiency. Pathologically, sulfatide accumulates in oligodendrocytes and macrophages in white matter where demyelination occur. Sulfatides may be found in kidney and gallbladder, in hepatocytes, Kupffer cells and epithelium of biliary ducts. Sulfatide deposits have a brownish or reddish color (metachromasia) when frozen sections are stained by cresyl violet or toluidine blue, contrasting with the blue cell nuclei of fibroblasts in Schwann cells. Electron microscopy localizes sulfatides to lysosomes, having a lamellar structure which frequently assumes a prismatic pattern.