And Laboratory Investigations

The sialic acid storage disorders include severe infantile sialic acid storage disease (ISSD) and a milder variant, Salla disease (SD). Intermediate variants have also been reported.

ISSD is a rare disorder, presenting in the neonatal period with coarse facial features, hepatospleno-megaly, and often ascites or hydrops. Cardiomegaly and heart failure may also be present. The patients usually display generalized hypotonia. The subsequent clinical course is invariably characterized by failure to thrive and grossly delayed development. Most patients have hypopigmented skin and fair hair. Albinoid fundi and optic atrophy may be present. Mild hypertrophy of the tongue and gums may be seen. A nephrotic syndrome may complicate the course of the disease. Spastic tetraparesis develops with increased muscle tone and hyperactive tendon reflexes. Seizures may occur. There are recurrent respiratory tract infections. Hypothyroidism has been reported infrequently. The age at death varies from soon after birth to 5 years of age.

SD occurs with a relatively high frequency in Finland. Pregnancy and the perinatal period are uneventful. The first clinical signs usually appear at 6-9 months of age and include hypotonia, ataxia, and nystagmus. Gradually the patients develop spasticity. Many develop signs of athetosis. Motor development is delayed, and about 30 % of the patients never walk without support. Speech development is also delayed, and the speech is dysarthric. The nystagmus disappears. Most patients acquire a divergent squint. Many patients are growth-retarded with a height below the second percentile. Mental development is delayed from early on, and most adults are severely mentally handicapped. Facial features may become coarse late in the course of the disease. Epileptic seizures may occur. Rarely, endocrine disturbances have been reported, including growth hormone deficiency and hypo-gonadotropic hypogonadism. The clinical course in SD patients is often static for many years, which delays evaluation for a metabolic disorder. The life span is relatively long. Most patients die in their thirties, but death in the seventies is also known to occur.

A few patients have been reported with a pheno-type intermediate between SD and ISSD, and in fact there is a phenotypic continuum between ISSD and SD.

Light microscopic examination of blood smears and bone marrow specimens reveal vacuolated lymphocytes in almost all ISSD patients and in most SD patients; young SD patients in particular may not have them. Electron microscopy of skin or conjunctival biopsy reveals vacuoles in many cell types including fibroblasts, smooth muscle cells, perineural cells, and Schwann cells. These vacuoles are bound by a single membrane and prove to be lysosomes. Most of them seem empty, but some contain small amounts of fibrillogranular material, membrane fragments, and occasional dark globules.

Dysostosis multiplex is found in about half of the patients with ISSD. Skeletal abnormalities are rare in SD and may include ovoid deformation of the vertebral bodies and a thickened calvarium of the skull. In SD EEG initially shows a slowing of background activity; in some patients epileptic activity is seen. With increasing age a gradual decrease in amplitude occurs; in adults a low-voltage EEG is a consistent finding. Motor and sensory nerve condition velocities are reduced in about half of the SD patients. So-matosensory evoked potentials are abnormal in the majority of SD patients, but visual and brain stem auditory evoked potentials are usually normal. The most prominent changes in nerve conduction and evoked responses are seen in the patients with the most severe disease.

Demonstration of increased urinary excretion of free sialic acid and sialic acid accumulation in cultured fibroblasts is the mainstay of the laboratory diagnosis in both ISSD and SD. The levels of sialic acid excretion vary widely among patients. The level reflects more or less the severity of the clinical disease. Confirmation of the diagnosis by DNA analysis is possible.

Prenatal diagnosis is possible by assay of free sialic acid in a chorionic villus biopsy or by molecular studies. In all families in which the mutation is known, the latter option is the most reliable, in particular in SD, in which the increase in sialic acid in chorionic villi of an affected fetus is less pronounced than in ISSD. The use of cultured amniotic fluid cells is less appropriate because the elevation of the free sialic acid content in these cells may be only moderate.

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