Adult-onset painful axonal polyneuropathy caused by a dominantNAGLUmutation

Abstract

Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes.

Recent advances in the genetic neuropathies

“…Recent additions to this list include mutations in NAGLU, ALS5/SPG11/KIAA8140 and VRK1 . Autosomal recessive mutations in NAGLU cause the severe childhood lysosomal storage disease, mucopolysacharidosis type III, however, a heterozygous NAGLU mutation has now been described in a large Canadian pedigree with painful axonal sensory neuropathy [18]. Recessive mutations in ALS5/SPG11/KIA8140 typically cause recessive hereditary spastic paraplegia with thin corpus callosum and axonal neuropathy, but can now also cause recessive CMT2 [19].…”

A novel frameshift deletion in NAGLU causing sanfilipo type III‐B in an Indian family

“…As this deleterious mutation is proposed to be present in junction of catalytic domain and TIM barrel domain of NAGLU protein it may affect the stability or binding of the ligand at the catalytic site. 5,6 As per the previous studies, there are various disease (MPS IIIB) causing variants in NAGLU and among these variants, frameshift and protein truncating variants reported in NAGLU gene have a very severe presentation and progression of MPS IIIB. 7 The earlier reported protein truncating mutations, that is, c.217_221dup5 (p.Val75fs), 503del10, Trp675X, Glu706X, and Arg297X shows severe phenotype where the median age of onset of 3 years, 7-9 however, the survival age differs with greater variability for these variants.…”

“…The frameshift deletion is leading to protein truncation after 299 amino acids. As this deleterious mutation is proposed to be present in junction of catalytic domain and TIM barrel domain of NAGLU protein it may affect the stability or binding of the ligand at the catalytic site …”

Diagnostic outcomes of exome gene panel sequencing in patients with unusual syndromic cleft lip/palate phenotypes

“…pathogenic NAGLU mutations present with a range of neurologic conditions including 364 peripheral neuropathy and sensory impairment. The disease has a late age of onset and 365 usually occurs between 18 and 61 years of age [49]. Considering the lack of phenotypic 366 similarity between the patient CL027 main features and CMT2V, it is unlikely that 367 NAGLU :c.311C>A (Ψ i =8) underlies the patient's condition.…”

“…Orofacial clefting (OFC) is a common congenital abnormality which has a prevalence of evaluated the utility of gene-panel sequencing for resolving molecular diagnoses in 48 general and consider patterns of sequence coverage across the FGD1 gene in particular 49 as an illustrative example. 50 Materials and methods 51 0.1 Patients phenotype 52 DNA samples from 14 unrelated male patients each with a tentative clinical diagnosis of 53 AAS were obtained through the Operation Smile clinic in Bogota, Colombia (Table 1).…”