Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes

Article type: Research Article

Authors: Chawla, Tanushree^a | Preethish-Kumar, Veeramani^a | Polavarapu, Kiran^{a; b} | Vengalil, Seena^a | Bardhan, Mainak^{a; c} | Puri, RatnaDua^d | Verma, Jyotsna^d | Christopher, Rita^e | Supriya, Manjunath^e | Nashi, Saraswati^a | Prasad, Chandrajit^f | Nadeesh, Bevinahalli^g | Nalini, Atchayaram^{a; *}

Affiliations: [a] Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India | [b] Children’s Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada | [c] Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India | [d] Department of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India | [e] Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India | [f] Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, India | [g] Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India

Correspondence: [*] Correspondence to: Dr. Atchayaram Nalini, Professor, Neuromuscular specialist, Department of Neurology, Neuroscience Faculty Block, National Institute of Mental Health and Neurosciences, Bangalore 560 029, India. Tel.: +91 80 26995139; Fax: +91 80 26564830; E-mail: atchayaramnalini@yahoo.co.in.

Abstract: Background:Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods:We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results:The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). Conclusion:We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

Keywords: Pompe disease, late-onset Pompe disease, LOPD, Rigid spine, peripheral neuropathy, anterior horn cell

DOI: 10.3233/JND-210728

Journal: Journal of Neuromuscular Diseases, vol. 9, no. 2, pp. 261-273, 2022