Familial Global Developmental Delay Secondary to β-Mannosidosis.

β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the MANBA gene. Two Indian siblings born out of a third-degree consanguineous marriage presented during late infancy with global developmental delay. On examination, both the siblings had hypotonia; hepatosplenomegaly was present in the first sibling whereas it was absent in the second sibling. Fundus evaluation, hearing assessment, and skeletal survey were normal in both siblings. Enzyme assay showed the absence of the β-mannosidase enzyme. Next-generation sequencing showed a homozygous variation of c.1317 + 1G>A in intron 10 of the MANBA (-) gene in the elder sibling. Sanger sequencing confirmed the same mutation in the homozygous state in both siblings and in the heterozygous state in both parents. Copyright:

INTRODUCTION

β-Mannosidosis is a rare lysosomal storage disorder of glycoprotein catabolism that is caused by a deficiency of β-mannosidase activity; this disorder leads to the accumulation of mannose-rich oligosaccharide chains. The disease is caused by mutations in the MANBA gene and it is extremely rare in humans. It has an estimated incidence of 0.1 per 100,000.[1] So far, 23 cases of β-mannosidosis in 18 families have been reported.[2] β-Mannosidosis was first described in 1986.[3] Here, we are reporting genetically proven β-mannosidosis in Indian siblings from a single family.

CLINICAL SUMMARY

The two siblings were born to a third-degree consanguineously married couple.

Case 1: The first male sibling, who was 3.5 years old, presented during late infancy with global developmental delay. Birth history was normal. The child was able to sit but was not able to walk, followed one-step commands, and spoke a few meaningful words. On examination, the child was stunted with a height of 85 cm (-3.87 SD), wasted with a weight of 9.4 kg (<–3SD), and had a head circumference of 45.5 cm (-3.07 SD), which was proportionate to body size. He had an open mouth and a protruding tongue, pallor, and hypopigmented hair [Figure 1A]. Systemic examination revealed poor eye contact, hyperactivity, inattention, hypotonia with normal reflexes, and mild hepatosplenomegaly. However, clinically, there were no skeletal, visual, or hearing abnormalities.

Figure 1

(A) Elder sibling showing open mouth with mild hepatosplenomegaly. (B) Younger sibling with poor eye contact. (C and D) MRI of the axial section T2WI of the brain of the elder sibling showing a hyperintense signal in periventricular and subcortical white matter with delayed myelination for age

Case 2: The younger male sibling of the child just mentioned, who was 18 months old, also had global developmental delay. The child had attained head control, was able to sit but was not able to walk, and only occasionally presented a social smile. On examination, he had a head circumference of 44.5 cm (-2.18SD); there was no coarse facies and no hepatosplenomegaly. Neurologically, there was poor eye contact, stereotypic movements, and there was hypotonia with normal reflexes. Clinically, there were no skeletal or hearing abnormalities [Figure 1B].

On investigation, complete hemogram, renal function test, liver function test, serum ammonia, serum lactate, and tandem mass spectroscopy were normal. Fundus evaluation for both siblings was normal, and there was no cherry-red spot. Hearing evaluation and the skeletal survey were normal in both siblings. Urinary testing for glycosaminoglycans was normal. MRI of the axial section T2WI of the elder sibling’s brain showed a hyperintense signal in the periventricular and subcortical white matter with delayed myelination for age [Figure 1C and D]. Serum β-mannosidase level was not detected (normal 51–137 nmol/h/mg). Targeted next-generation sequencing showed a homozygous pathogenic variant of NM_005908.4.c.1317 + 1G>A in intron 10 of the MANBA (-) gene. Sanger sequencing confirmed the same mutation in the homozygous state in both siblings and in the heterozygous state in both parents [Figure 2]. Both the siblings were on regular neurodevelopmental follow-up with stimulation but with no significant improvement. Genetic counseling was offered to the family.

Figure 2

Chromatogram showing the heterozygous status of the MANBA gene in father (A) and mother (B) and homozygous mutation of the MANBA gene in the elder sibling (C) and younger sibling (D)

DISCUSSION

The combination of developmental delay, hepatosplenomegaly, hypotonia, and behavioral difficulties in these children led to the suspicion of a lysosomal storage disorder. The differential diagnosis considered comprised mucopolysaccharidosis (MPS), gangliosidosis, mucolipidosis type II, sialidosis type II, and fucosidosis. As urinary GAG was negative, MPS was ruled out. Mucolipidosis type II was ruled out, as it usually presents with a more severe MPS phenotype in early infancy with a more aggressive course. Gangliosidosis was considered less likely, as there was no cherry-red spot, regression, ataxia, and epilepsy. The absence of a cherry-red spot, normal skeletal survey, and the course of the disease prevented us from considering sialidosis. The absence of the points mentioned earlier along with the absence of skin lesions and normal globus pallidi on neuroimaging enabled us to reasonably rule out the possibility of fucosidosis. Urine thin-layer chromatography to detect oligosaccharides as well as disaccharides was planned but could not be performed. β-Mannosidosis was considered as there was no cherry-red spot, normal skeletal survey and confirmed by absent β-mannosidase enzyme levels. The diagnosis was further confirmed by genetic studies.

β-Mannosidosis is an autosomal recessive disorder that has a highly variable clinical presentation. Presentations of this disorder can vary significantly, with some experiencing an early onset of symptoms and rapidly progressive illness, and others experiencing mild symptoms that can present later in childhood or adolescence. The most severely affected patients show developmental delay and mental retardation, but there are varying levels of severity and some patients may have a relatively mild disease. They can have intellectual disability/ developmental delay, behavioral disturbance, recurrent infections, and hearing loss. Severe neurological phenotypes such as epileptic encephalopathy, hydrocephalus, dysmorphic traits, and spinocerebellar ataxia have been reported.[4] Cooper et al.[3] reported on two Indian Hindu men who presented with intellectual disability and angiokeratomas but did not have any facial dysmorphism, hepatosplenomegaly, or radiological changes in their bones. Both had a deficiency of β-mannosidase. However, both the siblings did not have any angiokeratomas. The phenotype of human β-mannosidosis is heterogeneous, as described in a report of two siblings with the same mutation by Alkhayat et al.[5] A similar phenomenon was observed in siblings in our current article.

A homozygous 5I splice site variation in intron 10 of the MANBA gene that affects the invariant GT variant splice site of exon 10 was detected. The in silico predictions of the variant are damaging by MutationTaster2. By clinical and enzymatic correlation, the gene variant can be considered pathogenic. The research pertaining to a hematopoietic cell transplant for treatment is underway.[6]

The phenotype described in our article has not been previously observed in β-mannosidosis. Global developmental delay without regression, absence of coarse facies, no dysostosis multiplex on the skeletal survey, and hypomyelination on MRI of the brain have not been previously described. The reported novel pathogenic variant from the Indian subcontinent adds and broadens the existing genotype of this disease. This novel pathogenic variant would help in studying the genotype–phenotype correlation of these patients in the future in relation to demography.

CONCLUSION

In any child who presents with a developmental delay with or without hepatosplenomegaly in the absence of a cherry-red spot, β-mannosidosis should be considered as a differential diagnosis, in addition to other MPS and other storage diseases. Even coarse facies are not always present, and their phenotype is highly variable. Early diagnosis helps in prognosis and also for genetic counseling.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form/ forms, 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.