Therapeutic options for patients with neuraminidase deficiency

Neuraminidase deficiency (mucolipidosis I, sialidosis I and II) is a lysosomal disorder caused by NEU1 mutations. Neuraminidase deficiency has a spectrum of clinical presentations varying from early onset to late onset. The latter type is generally characterized by progressive symptoms of myoclonus, visual impairment, and ataxia. Here, we report this diagnosis in two sisters, currently aged 14 (patient 1) and 15 (patient 2). We describe their remarkable diagnostic history and ask for therapeutic advice. Patient 1 first experienced loss of visual acuity at the age of 12. Specifically, impaired perception of contrast and depth led to frequent falls and recurrent trauma. At 13, her worsening eyesight led to a traffic accident resulting in fractures of the lower leg. Ensuing ophthalmological examination revealed both-sided macular cherry-red spot, paleness and atrophic changes of optic disc, punctate opacities of the lens, and upbeat nystagmus. During the evaluation, it was noted that she had an intention tremor and ataxia. Her family history revealed that she had an older sister (patient 2) who had a long history of unexplained neurologic symptoms. Subsequent examination of patient 2 revealed ophthalmological features identical to those of her younger sister. At 9, patient 2 had presented with avascular necrosis of the right femur head. Spontaneous revascularization occurred gradually, resulting in mild femur head deformation only. Her hip pain, unsteady gait, and tiredness, however, worsened progressively. At 13, she developed mild ataxia and high frequency intention tremor, affecting all four limbs. A cerebellar cause was suspected but could not be indicated by neuroimaging or laboratory testing. Treatment for conversion syndrome was started but proved ineffective. Within a year, walking without support and writing by hand became impossible because of her worsening movement disorder. At evaluation in our center, neurologic examination revealed downbeat nystagmus, severe ataxia, severe intention tremor, and sporadic myoclonus of the limbs and eyelids. The combination of typical ocular and neurologic signs led to suspicion of LSD in both patients. Succeeding urinary analysis revealed oligosaccharide patterns characteristic for (galacto)sialidosis in both patients. Brain MRI showed no intracranial pathology in either. Activity of N-acetyl-neuraminidase in cultured fibroblast was 0.5 and 0.4 mmol/mg/h (15.0–45.0) for patients 1 and 2, respectively; both were diagnosed with neuraminidase deficiency. Sequencing of NEU1 revealed two known compound heterozygous mutations (c.1195_1200dup, p.His399_Tyr400dup; c.679G>A, p.Glu227Arg) in both patients. At present, patient 2 suffers from worsening eyesight, ataxia, tremor, and action myoclonus together with mild cognitive deterioration. Her movement disorder threatens independent functioning. Patient 1 mainly suffers from decreasing visual acuity (50% to 30% in four months); her movement disorder remains mild but she fears progression. No myoclonic seizures have occurred in either. Our current management focuses on adjustment and rehabilitation. As symptoms worsen during menstruation, both patients receive continuous oral contraception. Patient 2 is on a trial of clonazepam to reduce myoclonic jerks; the effects remain to be evaluated. Given the fast pace of deterioration of these subjects, we are searching for new/other therapies that might slow down disease progression or relieve symptoms.