To share our experience diagnosing a patient with adult-onset GM2 Gangliosidosis secondary to Hexosaminidase A deficiency

GM2 Gangliosidosis is a lysosomal storage disorder caused by deficiency of Hexosaminidase enzymes. Classically it affects children from infancy to age 10, with hypotonia, spasticity, blindness, seizures and premature death. We present the case of a 30-year-old female with 5 years of proximal muscle weakness and exercise intolerance, found to have GM2-Gangliosidosis.

30-year-old, developmentally normal female of Ashkenazi Jewish descent and no prior medical history presented for 5 years of bilateral, proximal leg weakness, muscle soreness and spasms with mild exercise and imbalance with ambulation. Prior to symptom onset she was an avid athlete and weightlifter.

On physical exam she had normal bulk and tone, no fasciculations or myotonia. Strength, sensation and reflexes were normal.  Cerebellar exam showed mild dysmetria on finger-to-nose testing in the left arm and heel-to-shin bilaterally.

CK, ESR, CRP, Aldolase, TSH, Lactic acid and pyruvic acid were normal. Nerve conduction testing was normal. EMG revealed diffusely reduced recruitment, motor unit enlargement along with positive waves, fibrillations and fasciculations in proximal and distal muscles of the arm and leg, consistent with motor neuron disease.  Brain MRI revealed pronounced cerebellar atrophy.

Genetic testing revealed 2 pathogenic mutations of the HEXA Gene, coding for lysosomal enzyme β -hexosaminidase A: c.1274_1277dup (p.Tyr427Ilefs*5) and c.805G>A (p.Gly269Ser) associated with GM2-Gangliosidosis. Hexosaminidase activity in the blood revealed 0% Hexosaminidase A.

Adult onset GM2 Gangliosidosis is rare, however can present with proximal muscle weakness secondary to motor neuron disease, ataxia, and psychiatric disorders. The largest cohort published consisted of 57 cases of adult-onset disease. Similar to our patient, the most common presenting symptom was lower extremity weakness and majority were compound heterozygous for HEXA or B mutations.  Diagnosis is made with genetic testing and enzyme activity level.