In this study, we aim to further define the phenotypic characteristics of the UBQLN2 mutations in the ALS patients from Turkey.

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease (MND), caused by degeneration of upper and lower motor neurons. UBQLN2 gene, which encodes ubiquilin-2, a member of the ubiquitin-like protein family, has been associated with X-linked ALS.

Clinical and genetic findings of six patients and five asymptomatic carriers with UBQLN2 variants from five unrelated families from Turkey diagnosed with possible, probable, or definite ALS by El Escorial criteria at the Department of Neurology, Istanbul Faculty of Medicine were evaluated. The samples were collected with the approval of the relevant institutional ethics boards, and informed written consent was obtained from each participant.

Two of the symptomatic and four of the asymptomatic patients were female.  The mean age of onset was 20.7±7.84 (range 12-36) years. The mean age of asymptomatic patients was 48.2 (range 35-76) years. One of our patient had Madras MND. Three of them presented with weakness and muscle wasting of one hand, three with bulbar dysfunction symptoms, and one with foot drop. Four of our patients had prominent lower motor neuron signs at the onset of the disease. Five patients died during follow-up because of respiratory complications, mean time to death after the onset of disease was 8.4 years (range 4-14 years). Four distinct missense variants (P506S, P525S, M392I, S340I) were found in our families.

This is the largest cohort from Turkey, indicating genotypic and phenotypic heterogeneity of UBQLN2 mutations. The S340I change was identified in 3 unrelated families from Turkey previously. M392I variant was found in two of our patients with distinct phenotype (Madras MND and juvenile onset slowly progressive MND). Further analyses are needed to clarify the pathogenicity of the M392I variant of UBQLN2.