Alpha-Mannosidosis from India due to a Novel Pathogenic Variant in MAN2B1 Gene.

Alpha-mannosidosis is a lysosomal storage disorder caused by mutations in MAN2B1 gene. A 7-year-old girl child, born of a consanguineous marriage, presented with developmental delay, seizures, and hearing impairment. On examination, she had coarse features without hepatosplenomegaly. On investigations, low levels of the enzyme alpha-mannosidase level were observed. Targeted next-generation sequencing revealed a novel pathogenic variant p.Trp469Ter on exon 11 of MAN2B1 gene. Copyright:

INTRODUCTION

Alpha-mannosidosis is a rare lysosomal disorder caused by deficiency of alpha-mannosidase, a lysosomal enzyme required for the degradation of N-linked oligosaccharides. On the basis of severity, it is classified into a severe form, type 1 with early death due to infections and hepatomegaly,[1] and a milder form, type 2 with hearing loss, mental retardation, and slow progression into adulthood.[2] The prevalence of the disease is estimated to be one in million live births.[3] Here, we are reporting a first case of alpha-mannosidosis due to a novel pathogenic variant from India to the best of our knowledge.

CASE REPORT

A 7-year-old girl, born to a consanguineously married couple, presented with developmental delay, seizures, and hearing impairment. Birth history was normal. Developmentally, the child delayed in all milestones. At presentation, she was able to walk with support, required help in activities of daily living, could speak few words with meaning in phrases, and was going to special education school. She had fever-triggered seizures twice and progressive hearing impairment since 2 years of age. On examination, head circumference was found to be 50 cm and weight was 23.3 kg, both were normal for age. She had coarse facies, widely spaced teeth, synophrys, macroglossia, short neck, and bilateral equinovalgus and hammer toe deformity [Figure 1A and B]. On neurological examination, tone was increased in all four limbs with a power of 4/5 (Medical Research Council grade), exaggerated deep tendon reflexes, and extensor planter bilaterally. Ataxia was present. No hepatosplenomegaly was observed. Fundus examination was normal.

Figure 1

(A) Clinical photograph showing coarse facies, widely spaced teeth, synophrys, open mouth (white arrow), and short neck. (B) Photograph showing bilateral equinovalgus (black arrow) and hammer toe deformity. (C) X-ray of hand showing osteopenia but no dysostosis multiplex (black arrow). (D) Fluid-attenuated inversion recovery axial view of MRI of brain showing hyperintensities (white arrow) in bilateral periventricular region. (E and F) Sagittal section of MRI of brain showing atrophy of body corpus callosum (white arrow) and superior cerebellar atrophy (white arrow)

On investigations, complete hemogram, renal, liver function, serum ammonia, serum lactate, and tandem mass spectroscopy were found to be normal. Urine for glycosaminoglycans was normal. Skeletal survey revealed osteopenia but no dysostosis multiplex [Figure 1C]. Brain stem–evoked response audiometry (BERA) was suggestive of hearing impairment. Magnetic resonance imaging (MRI) of brain showed T2 hyperintensities in periventricular white matter, thin corpus callosum, and superior cerebellar atrophy [Figure 1D, E, and F]. Serum alpha-mannosidase level was low, 4.2 nmol/h/mg (109–580 nmol/h/mg). A homozygous nonsense pathogenic variant c.1406G>A (p.Trp469Ter) in Exon 11 of MAN2B1 gene was detected in targeted next-generation sequencing, and it was confirmed by Sanger sequencing.

DISCUSSION

Here we describe a child with developmental delay, hearing loss, fever-triggered seizures with mucopolysaccharidosis (MPS) phenotype secondary to alpha-mannosidosis. The disease can have heterogeneity not only in clinical presentations but also at molecular level.[4] Clinical features include immune deficiency, mild-to-moderate skeletal abnormalities in the form of dysostosis multiplex, scoliosis and sternal deformities, hepatosplenomegaly, and dysmorphic features in the form of forehead prominence, rounded eye brows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Neurological features include impairment of cognition and speech, muscle weakness, ataxia, and sensorineural hearing loss. There can be cardiac or renal manifestation as this is a multisystem disease.[56] The observed clinical features were the coarse features as described earlier with skeletal abnormalities noted as equinovalgus deformity with osteopenia. Neurologically, she had ataxia, cognitive, and speech delay. The patient had no renal or cardiac involvement.

Differential diagnoses of MPS phenotype considered in this child were MPS type 3, mucolipidosis type 3, and sialidosis type 2. MPS was ruled out as urine glycosaminoglycans were absent. Mucolipidosis 3 was ruled out as they usually present with predominant skeletal problems. Sialidosis type 2 was ruled out as the patient had no cherry red spot, and it usually presents very early with more severe phenotype. Mannosidosis was considered as the patient had early-onset hearing loss, and the examination showed skeletal deformities and widely spaced teeth. Several neuroimaging features are described, which include cerebral atrophy,[7] demyelination, and calvarial thickening.[8] In this child, MRI of brain showed white matter hyperintensities in periventricular white matter, thinning of corpus callosum, and superior cerebellar atrophy.

The variant p.Trp469Ter is a stop codon and results in premature truncation of the protein at codon 469. This variant has not been reported in the 1000 genome and ExAC. The variant is damaging as per in silico prediction Mutation Taster. With clinical and functional correlation, the mutation can be considered pathogenic in the current scenario. Early diagnosis is important as bone marrow transplantation is considered as a therapeutic option.[9] The unusual features in this child are no recurrent infections, no skeletal changes such as dysostosis multiplex, and no hepatosplenomegaly and a novel MAN2B1 variant. As per our knowledge, this is the first case report from India.

CONCLUSION

Alpha-mannosidosis should be considered in individuals with intellectual disability, mild coarse facies, and hearing impairment in addition to other MPSs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.