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Year : 2023  |  Volume : 3  |  Issue : 2  |  Page : 77-80

Rare Coexistence of SLC6A9 and TOR1A Gene Mutations in a Neonate Presenting with Hereditary Hyperekplexia and Arthrogryposis Multiplex Congenita: A Case Report with Review of Literature

Department of Pediatrics, Government Medical College, Vadodara, Gujarat, India

Date of Submission24-Jan-2023
Date of Decision01-Apr-2023
Date of Acceptance25-Apr-2023
Date of Web Publication24-May-2023

Correspondence Address:
Dr. Bhavya Patel
Department of Pediatrics, Government Medical College, Vadodara, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_25_23

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Background: Neonatal hyperekplexia is a rare nonepileptiform disorder characterized by an exaggerated startle reflex associated with generalized hypertonia. We report a newborn with mutation in the glycinergic inhibition pathway resulting in hyperekplexia, associated with features of arthrogryposis multiplex congenita. Clinical Description: A 3-day-old newborn born at term vaginally cried immediately after birth and presented with lethargy, poor cry, and abnormal clonic movements of all four limbs. On examination, there was hyperreflexia and hypertonia in all four limbs along with dislocation of the right knee joint. Blood investigations, including tandem mass spectrometry, serum ammonia, serum, and cerebrospinal fluid glycine levels, were normal, ruling out inborn errors of metabolism responsible for hyperekplexia and arthrogryposis. The magnetic resonance imaging (MRI) brain and electroencephalogram were normal, while the MRI spine showed kyphosis. The genetic evaluation showed heterozygous missense mutation in exon 6 of the SLC6A9 gene and homozygous mutation in the TOR1A gene, which explained the hyperekplexia and the arthrogryposis multiplex congenita. Management and Outcome: The patient received supportive care. Oral clonazepam and levetiracetam were started in view of hypertonia and clonic spasms. Feeding was given by intragastric tube as he had poor suck–swallow coordination. Conclusions: This case highlights an interesting and extremely rare combination of hereditary hyperekplexia and arthrogryposis multiplex congenita existing together in the same patient, confirmed by the corroborating genetic mutations. Awareness of such conditions among pediatricians is essential to order appropriate genetic evaluations and treatment accordingly.

Keywords: Arthrogryposis multiplex congenita, glycine encephalopathy, GLYT1 dysfunction, SLC6A9, TOR1A

How to cite this article:
Patel B, Bhatt S, Chanpura V. Rare Coexistence of SLC6A9 and TOR1A Gene Mutations in a Neonate Presenting with Hereditary Hyperekplexia and Arthrogryposis Multiplex Congenita: A Case Report with Review of Literature. Indian Pediatr Case Rep 2023;3:77-80

How to cite this URL:
Patel B, Bhatt S, Chanpura V. Rare Coexistence of SLC6A9 and TOR1A Gene Mutations in a Neonate Presenting with Hereditary Hyperekplexia and Arthrogryposis Multiplex Congenita: A Case Report with Review of Literature. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 6];3:77-80. Available from: http://www.ipcares.org/text.asp?2023/3/2/77/377514

Hereditary hyperekplexia is a condition in which neonates have generalized hypertonia and an exaggerated startle reflex to external stimuli. Various gene mutations have been implicated in the pathogenesis of neonatal hyperekplexia, all of which result in the disruption of normal glycine signaling in neurons in the spinal cord and the brain stem, which causes exaggerated startle reactions.[1] Arthrogryposis multiplex congenita is a term for the development of nonprogressive contractures involving one or more joints since birth. In this case, we report unique etiology and presentation of neonatal hyperekplexia along with arthrogryposis multiplex congenita.[2]

The incidence of each of these conditions individually is quite rare, and the simultaneous presence of both clinical entities in the same individual is even rarer.

  Clinical Description Top

A full-term male neonate, born out of nonconsanguineous marriage, second in birth order, delivered by vaginal delivery, cried immediately after birth, liquor was clear and was referred to us on the 3rd day of life with lethargy, abnormal clonic movements of all four limbs, stridor, and poor feeding. In antenatal history, the mother was on regular follow-up with all antenatal scans being normal, liquor was adequate and fetal movements were well perceived and there was no history of antenatal illness. There was no family history of any neurological illness or seizures, and the baby's elder sibling was alive and healthy at 3 years of age. On examination, the baby was lethargic and normothermic, heart rate was 132/min, respiratory rate was 46/min, and maintaining 96% of saturation on room air. The baby's birth weight was 3 kg, head circumference was 32.5 cm, and length was 48 cm, all being appropriate for his gestational age.

The patient was having an exaggerated startle reflex, with poor suck–swallow coordination. The tone in all four limbs was increased and there was hyperreflexia with bilateral ankle clonus. Even when the patient fell asleep, hyperreflexia and hypertonia persisted. On examination, the right-sided knee was found to be dislocated. On back and spine examination, abnormal curvature was seen. Abdominal examination revealed bilateral irreducible swelling over the bilateral inguinoscrotal regions [Figure 1]. Respiratory and cardiovascular examination were normal. The stool and urine frequency were adequate.
Figure 1: Infant with increased tone and bilateral inguinal hernia

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Investigations done on the 4th day of life showed hemoglobin 12.6 g/dL, total white cell count of 13,660/mm3, platelet count: 264,000/μL, ionized calcium 1.06 mg/dL, urea 26 mg/dL, creatinine 0.6 mg/dL, and total bilirubin was 3.2 mg/dL. Creatine phosphokinase 21,454, cerebrospinal fluid (CSF) routine and microscopy showed <5 cells, protein 150 mg/dL, sugar 62 mg/dL, concurrent blood sugar 82 mg/dL, with sterile cultures. The thyroid profile showed total T3: 1.9 ng/dL, total T4: 15.3 ng/dL, and TSH: 6.8 ng/dL, and serum ammonia was 77.00 μ/dL (range 9–35 μ/dL).

On further investigation, ultrasound abdomen was suggestive of right adrenal hemorrhage with bilateral inguinal hernia containing bowel loops. The magnetic resonance imaging (MRI) of the brain and electroencephalogram (EEG) was normal, while MRI spine was suggestive of kyphosis at the dorsolumbar region and X-ray knee was suggestive of congenital dislocation of the right knee. The multiple bony abnormalities were suggestive of arthrogryposis multiplex congenita.

Considering the possibility of inborn error of metabolism, tandem mass spectrometry was done, which turned out to be normal. Further evaluation showed that CSF glycine level was 5.36 mmol/L, plasma glycine level was 432.74 mmol/L, and both were within the normal range. The whole exome study was positive for a heterozygous missense mutation in exon 6 of the SLC6A9 gene that results in the substitution of serine for glycine at codon 295, which explained the neonatal hyperekplexia and glycine encephalopathy. In addition, there was a homozygous mutation in the TOR1A gene that results in a frameshift and premature truncation of the protein 13 amino acids downstream to codon 264, which clinically presented as arthrogryposis multiplex congenita.

Thus, the baby was diagnosed to be a case of glycine encephalopathy with hyperreflexia associated with arthrogryposis multiplex congenita.

  Management and Outcome Top

The baby was started on oral clonazepam (0.3 mg/kg/day in three divided doses) and levetiracetam (30 mg/kg/day in 2 divided doses), although clonic spasms persisted. As the patient required prolonged intragastric feeding, gastrostomy was planned, and the baby was discharged. For the arthrogryposis component, orthopedic advice was taken and conservative management was advised in view of the general condition.

  Discussion with Review of Literature Top

In the case described above, we encountered two different and rare clinical conditions: neonatal hyperekplexia and arthrogryposis multiplex congenita together, in the same neonate, a combination rarely found in literature.

Neonatal hyperekplexia is a rare nonepileptic disorder characterized by an exaggerated persistent startle reaction to various stimuli, associated with generalized stiffness. It can be an inherited neuronal disorder caused by genetic defects such as GLRA1, SLC6A5, GLRB, GPHN, ARHGEF9, and SLC6A9, leading to dysfunction of glycinergic inhibitory transmission.[3],[4],[5],[6] The condition may also be acquired when there is a pontine pathology and can be caused by metabolic abnormalities like nonketotic hyperglycinemia.[4] The difference between glycine encephalopathy due to nonketotic hyperglycinemia and SLC6A9 gene mutation is shown in [Table 1].[7],[8]
Table 1: Difference between glycine encephalopathy due to nonketotic hyperglycinemia and SLC6A9 gene mutation[7]

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The role of glycine is that it activates inhibitory glycine receptors and is a co-agonist for excitatory NMDA receptors. Dysregulation in glycine has been associated with hyperekplexia.[1] Glycine levels are controlled by degradation by the glycine cleavage system in which glycine metabolizes into serine and to a lesser extent by the glycine transport system mediated by sodium-dependent carriers GLYT1 and GLYT2. Of both, GLYT1 regulates extracellular glycine levels predominantly. The SLC6A9 gene located on chromosome 1p34.1 encodes GlyT1, which is located on the plasma membrane, chiefly in glial cells and neurons.[2] Its main function is to modulate glycine levels in the synapse by transporting glycine from the synaptic cleft into cells. In our case, the whole exome study showed a SLC6A9 missense heterozygous mutation leading to GLYT1 dysfunction presenting as a rare clinical presentation of glycine encephalopathy with normal glycine level. The incidence of glycine encephalopathy in nonketotic hyperglycinemia is 1 among 60,000. However, glycine encephalopathy with normal glycine levels due to GLYT1 dysfunction because of SLC6A9 mutation is the rarest variant.[9] To date, only six cases of such encephalopathy due to GLYT1 dysfunction were noted [Table 2].[7],[10]
Table 2: Review of literature showing prior published cases of glycine encephalopathy with mutations in SLC6A9 mutation causing glycine transporter 1 dysfunction

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Clinically, the patient presents with difficulty in swallowing, weak cry, joint laxity, apnea, hyperekplexia, and failure to thrive, along with axial hypotonia, startle-like clonus, facial features of trigonocephaly, long myopathic facies, retrognathia, and microcephaly.[7] Examination findings of our patient included hypertonia in all four limbs, exaggerated reflexes, and bilateral ankle clonus with bilateral irreducible inguinal swelling with normal facial features. However, there was neither microcephaly nor facial dysmorphism. The MRI of the brain may show atrophy in the caudate nucleus, white matter changes, or normal myelination. EEG is normal in most patients, with few of them showing generalized background slowing with no epileptiform discharges. Our case showed normal MRI, EEG, and normal values of CSF glycine and plasma glycine levels.

Although glycine encephalopathy has no curative treatment, it appears that in individuals with defective glycine cleavage system enzymes activity, early aggressive treatment with sodium benzoate, to reduce plasma glycine and NMDA receptor blockers (e.g., dextromethorphan) can improve neurodevelopmental outcomes,[9] but this subtype of glycine encephalopathy with normal glycine level described here, did not respond to this therapy. Treatment of abnormal hyperclonic movements and hypertonia for newborns and infants is benzodiazepines like clobazam. Other drugs used with variable effects include levetiracetam and topiramate. Felbamate has been successful in some children with difficult-to-treat seizures.[11]

Thus, management is largely symptomatic with a very poor prognosis. GLYT1 encephalopathy requires a multidisciplinary team approach, including pediatricians, neuro physicians, physiotherapists, occupational therapists, and orthopedic surgeons. Neonates with glycine transporter 1 encephalopathy are at risk of gastroesophageal incoordination, sucking, and swallowing difficulties, which may lead to aspiration, malnutrition, and failure to thrive. In many patients, a feeding tube, such as a gastrostomy tube, would be efficient to ensure the patient receives enough calories and avoids recurrent aspirations.

Arthrogryposis was another associated feature in our case. Amyoplasia is the most common form of arthrogryposis, multiple joint contractures with more involvement of distal joints, the usual feature is club foot. Congenital contractures are believed to be due to decreased fetal movements resulting in excessive connective tissue formation around the joints, resulting in joint stiffness. Oligohydramnios, maternal infections, and teratogenicity can decrease fetal movements.[11] In our patient, antenatal history was normal. Further, genetic evaluation by the whole exome study showed a mutation in the TOR1A gene located at the long arm of chromosome 9, inherited as an autosomal recessive form and present as joint contractures, hypertonia, and dystonia. The TOR1A gene protein called torsion A is found in the space between the nuclear envelope and the endoplasmic reticulum. Dysfunction due to TOR1A gene mutation leads to generalized dystonia and bony contractures. The incidence of arthrogryposis due to DYT1 dysfunction is 20 in 1 million.[12],[13] Management requires surgical intervention and physiotherapy to increase the range of movements.

  Conclusion Top

Hereditary hyperekplexia is a rare and underdiagnosed disorder, manifesting just after birth. Knowledge about this condition would be helpful in the prevention of life-threatening complications like apnea. Our case highlights that glycine encephalopathy can rarely present as neonatal hyperekplexia with normal serum glycine and CSF glycine levels, due to heterozygous mutation in the SLC6A9 gene. Further, this rare disorder may be associated with another rare condition like arthrogryposis multiplex congenita, due to homozygous mutation of the TOR1A gene.

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.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Matsumoto J, Fuhr P, Nigro M, et al. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol 1992;32:41-50.  Back to cited text no. 1
Devadas S, Malladad A, Sabapathy S. Arthrogryposis multiplex congenita. Perinatology 2020;21:129-32.  Back to cited text no. 2
Carta E, Chung SK, James VM, et al. Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. J Biol Chem 2012;287:28975-85.  Back to cited text no. 3
Chung SK, Bode A, Cushion TD, et al. GLRB is the third major gene of effect in hyperekplexia. Hum Mol Genet 2013;22:927-40.  Back to cited text no. 4
Rees MI, Harvey K, Pearce BR, et al. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet 2006;38:801-6.  Back to cited text no. 5
Thomas RH, Drew CJ, Wood SE, et al. Ethnicity can predict GLRA1 genotypes in hyperekplexia. J Neurol Neurosurg Psychiatry 2015;86:341-3.  Back to cited text no. 6
Alfadhel M, Nashabat M, Qahtani HA, et al. Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Hum Genet 2016;135:1263-8.  Back to cited text no. 7
Bharti K, Bajaj N. Nonketotic hyperglycinemia. Perinatology 2017;18:28-30.  Back to cited text no. 8
Alfallaj R, Alfadhel M. Glycine transporter 1 encephalopathy from biochemical pathway to clinical disease: Review. Child Neurol Open 2019;6:2329048X19831486.  Back to cited text no. 9
Kurolap A, Armbruster A, Hershkovitz T, et al. Loss of glycine transporter 1 causes a subtype of glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid glycine. Am J Hum Genet 2016;99:1172-80.  Back to cited text no. 10
Mallappa A, Bali S. P101 Intractable Seizures in a neonate-case report. Arch Dis Child 2019;104:A196-7.  Back to cited text no. 11
Kiefer J, Hall JG. Gene ontology analysis of arthrogryposis (multiple congenital contractures). Am J Med Genet C Semin Med Genet 2019;181:310-26.  Back to cited text no. 12
Asanuma K, Ma Y, Okulski J, et al. Decreased striatal D2 receptor binding in non-manifesting carriers of the DYT1 dystonia mutation. Neurology 2005;64:347-9.  Back to cited text no. 13


  [Figure 1]

  [Table 1], [Table 2]


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