OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: SIAT9

Infantile Epilepsy Syndrome
Lactosylceramide alpha-2,3 sialyltransferase deficiency

Seizures
Developmental delay
Failure to thrive
Blindness

GM3 Synthase Deficiency

Clinical Characteristics

General description (for patients):

This neonatal developmental disorder has its onset in the first months of life, usually beginning with poor feeding and generalized seizures resistant to anticonvulsants. There is a complete absence of responsiveness to most social stimuli and infants seem to take little interest in their surroundings. They often seem highly irritable. They are unable to sit alone, or to communicate verbally.  They eventually become unable to take oral nourishment and require tubal feedings. They often seem limp and floppy.  Poor vision is present.

Medical description: 

This ganglioside disorder is due to the loss of function of an enzyme at the head of the chain synthesizing most complex gangliosides from dietary lactosylceramide. The result is a severe infantile seizure disorder, with onset of generalized tonic-clonic seizures as well as other types within the first year of life. They have severe developmental stagnation sometimes with evidence of regression. Other manifestations in the first year of life include irritability, poor feeding, vomiting and generalized failure to thrive. Affected individuals never sit alone, nor walk, and are nonverbal. Non-purposeful arm movements with a chorioathetoid component may be present. Generalized hypotonia with reduced or absent upper limb reflexes can be present although lower limb reflexes are often brisk. Electroencephalograms may show multifocal epileptiform discharges superimposed on diffuse and slow background activity. MRI shows no structural changes early but at older ages there is diffuse atrophy.  The optic nerves are pale.

Genetics:

The responsible gene (SIAT9) is located at 2p-p11.2. The mutation (694C>T) in exon 8 results in premature termination of synthesis of the GM3 synthase enzyme.

Treatment:

No treatment is known beyond palliative care. It is unknown if the clinical disease is due to a lack of downstream gangliosides or the toxic effect of increased levels of lactosylceramide and alternate overproduction of its derivatives.

Prognosis:

Individuals may live into adolescence but in a general vegetative state requiring total custodial care. They are usually blind and non-responsive to their environment.

Ancillary treatments and support:

General custodial care and gastric tube feeding are necessary. Good pulmonary hygiene is recommended to prevent bronchitis and pneumonitis.

Specialists and specialty centers:

Neurologists are helpful in attempts to modify and control seizures. Acute hospitalization may be required for complications of an urgent nature.

References:

Simpson, M.A., Cross, H., Proukakis, C., Priestman, D.A., Neville, D.C.A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M.A., Dwek, R.A., Butters, T.D., Platt, F.M., and Crosby, A.H.: Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nature Genet. 36: 1225-1229, 2004. PubMed ID: 15502825

Farukhi, F., Dakkouri, C., Wang, H., Wiztnitzer, M., and Traboulsi, E.I.:  Etiology of vision loss in ganglioside GM3 synthase deficiency.  Ophth. Genet. 27: 89-91, 2006. PubMed ID: 17050284

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