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Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 97-99

Follow-up and novel gene identification of the X-linked myotubular myopathy in Indian family

1 Department of Pediatrics and Neonatology, KEM and Ratna Hospital, Pune, Maharashtra, India
2 Department of Pediatrics and Neonatology, Cloudnine Hospital, Pune, Maharashtra, India

Date of Web Publication13-Apr-2017

Correspondence Address:
Amit Nigade
Cloudnine Hospital, “Axon Building” Survey No 28/1, Bhamburda, Near Sakhar Sankul, Shivajinagar, Pune - 411 005, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_31_16

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Myotubular myopathy (MTM) is one of the rare types of the congenital myopathy. There are three types of inheritance documented, namely, X-linked recessive, autosomal recessive, and autosomal dominant. X-linked myotubular myopathy (XLMTM) is most common and severe in the spectrum. Usually, it is characterized by severe hypotonia and difficulty in establishing spontaneous respiration at birth in affected males. The incidence of XLMTM is estimated at 2/100,000 male neonates. The disease affects only male neonates and is linked to mutation in MTM1 gene, located on Xq28 and coding of myotubularin. Identification of the MTM1 gene mutations is of great importance as it allows confirmation of diagnosis and determination of carrier status, which is necessary for the genetic counseling. We report one case of MTM confirmed by the MTM1 gene mutation in Indian family with a history of neonatal death.

Keywords: Congenital hypotonia, myotubular myopathy gene, X-linked myotubular myopathy

How to cite this article:
Kadam S, Nigade A. Follow-up and novel gene identification of the X-linked myotubular myopathy in Indian family. J Clin Neonatol 2017;6:97-9

How to cite this URL:
Kadam S, Nigade A. Follow-up and novel gene identification of the X-linked myotubular myopathy in Indian family. J Clin Neonatol [serial online] 2017 [cited 2020 Aug 10];6:97-9. Available from: http://www.jcnonweb.com/text.asp?2017/6/2/97/204512

  Introduction Top

X- linked Myotubular Myopathy is a rare congenital muscle disorder associated with high neonatal and early childhood mortality. Histologically, it has small fibers showing central area devoid of myofibrils and mitochondrial aggregates around centrally loculated, often large nuclei.[1] Van Wijngaarden et al. first described it in 1965, and most infants died of the respiratory failure with in the 1st year of life.[2] The disease is caused by mutations in MTM1 gene and coding of myotubularin, a phosphate involved in signal transduction networks, which are active in the process of differentiation and maturation of the muscle fibrils.[3] Genetic predisposition is like, If the mother is a carrier, each sib has 50% chance of inheriting the MTM1 pathogenic variant. Males who inherit will be affected while females who inherit will be carriers and will generally not be affected. So genetic counseling plays vital role in planning future pregnancies.

  Case Report Top

A male neonate of healthy, nonconsanguineous Indian couple was born by cesarean section at 36 weeks of gestation (Apgar 1'5 5'7: birth weight 2.6 kg). Antenatally, the mother had polyhydramnios and she also noticed reduced fetal movement during pregnancy. The infant was born floppy with a weak cry and poor respiratory efforts. The infant was intubated due to gasping respiration and admitted in the Neonatal Intensive Care Unit. Lack of respiratory movements, generalized hypotonia, and absence oftendon reflexes were noted. The infant was extremely floppy and had a frog-like posture. No other external visible malformations were noted. The infant had a series of investigations to rule out the cause. Spinal muscular atrophy Type 1 and 2 was ruled with the help of polymerase chain reaction amplification and restriction endonuclease digestion technique [Figure 1]. There was no evidence of metabolic disorder by routine investigations. Cerebral ultrasound and subsequent magnetic resonance imaging [Figure 2] were normal. Open biopsy of the calf muscle was performed which showed characteristic features of myotubular myopathy (MTM) [Figure 3]. The infant required prolonged ventilation and unable to extubate from respiratory support at several attempts because of weak respiratory movements. Genetic study was performed to assist the diagnosis. The gene study showed previously unreported mutation c.963_964insC (p. Lys322fs) in exon 10 and confirmed the diagnosis of MTM1-related myopathy [Figure 4]. The mother's blood was also suggestive of the heterozygous mutation at the same site [Figure 5] and she is the carrier of the disease. Unfortunately, the infant died of cardiorespiratory arrest and prolonged ventilator dependency. Genetic counseling was offered in the next pregnancy.
Figure 1: Molecular study for spinal muscular atrophy gene by polymerase chain reaction amplification and restriction endonuclease digestion technique

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Figure 2: Magnetic resonance imaging of the brain of infant - . reported as normal

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Figure 3: Muscle biopsy report

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Figure 4: DNA sequencing of the infant

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Figure 5: DNA sequencing of the mother

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During the next pregnancy, amniocentesis was performed and it was found that both twin girls are not the carrier of the disease. Now, after a long period of the battle, the family is happy and contended about new arrivals in the family.

  Discussion Top

Congenital hypotonia is a common presentation in the neonatal period. Some of them have genetic cause and are associated with a risk of recurrence. A high percentage of these patients require mechanical ventilation from birth throughout the duration of life.[4] Hence, it requires systematic and comprehensive approach to find the cause.

Congenital myopathy is one of the causes of hypotonia in the neonatal period and also has a genetic predisposition. X-linked myotubular myopathy (XLMTM) occurs less frequently than the more common central core, multiminicore disease, and nemaline rod myopathies. The incidence of XLMTM is not known in Indian population. Muscle biopsy and gene analysis are two tools which are helpful in diagnosing the disorder.

A large number of the missense, nonsense, and splice-site mutations have been described in MTM1 gene as a causative of XLMTM.[5] Mutations are distributed throughout the gene although there is some clustering in exons 3, 4, 8, 9, 11, 12, and 13. Identification of the pathogenic mutation in the DNA of the mother provides a sound basis for the genetic counseling, especially when the mother is asymptomatic as in the present case.

In our case, mutation was c.963_964insC (p. Lys322fs) in exon 10 and the mother was the carrier. Diagnosis of the mutation in XLMTM has prenatal implications in future pregnancies by detecting mutation by chorionic villus biopsy and amniocentesis.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Wallgren-Pettersson C, Jungbluth H. Congenital myopathies. In: Rimoin DL, editor. Emery and Rimoin's Principles and Practice of Medical Genetics. 5th ed., Vol. 3. London: Churchill Livingstone; 2007. p. 2971-3.  Back to cited text no. 1
van Wijngaarden GK, Fleury P, Bethlem J, Meijer AE. Familial “myotubular” myopathy. Neurology 1969;19:901-8.  Back to cited text no. 2
Biancalana V, Caron O, Gallati S, Baas F, Kress W, Novelli G, et al. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with A very mild phenotype. Hum Genet 2003;112:135-42.  Back to cited text no. 3
Collins JE, Collins A, Radford MR, Weller RO. Perinatal diagnosis of myotubular (centronuclear) myopathy: A case report. Clin Neuropathol 1983;2:79-82.  Back to cited text no. 4
Laporte J, Biancalana V, Tanner SM, Kress W, Schneider V, Wallgren-Pettersson C, et al. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 2000;15:393-409.  Back to cited text no. 5


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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