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Year : 2021  |  Volume : 24  |  Issue : 1  |  Page : 98-101

X linked infantile epileptic encephalopathy due to SMC1A truncating mutation

EN1 Neuro Pediatric Neuroscience Centre, BKC Annexe, LBS Marg, Kurla, Mumbai, Maharashtra, India

Date of Submission17-Oct-2019
Date of Acceptance03-Nov-2019
Date of Web Publication03-Jan-2020

Correspondence Address:
Dr. Neeta Ajit Naik
EN1 Neuro Pediatric Neuroscience Centre, BKC Annexe, LBS Marg, Kurla, Mumbai - 400 070, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_518_19

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How to cite this article:
Naik NA, Shah AR. X linked infantile epileptic encephalopathy due to SMC1A truncating mutation. Ann Indian Acad Neurol 2021;24:98-101

How to cite this URL:
Naik NA, Shah AR. X linked infantile epileptic encephalopathy due to SMC1A truncating mutation. Ann Indian Acad Neurol [serial online] 2021 [cited 2022 Oct 7];24:98-101. Available from:

Dear Sir,

Till date, PCDH19 was the only well described X linked disorder associated with the syndrome of 'Epilepsy with Mental Retardation limited to Females (EFMR).[1] Recently pathogenic truncating variants in SMC1A gene have been reported in females with similar presentation. Their characteristic phenotype differs from SMC1A related Cornelia de Lange syndrome (CdLS).[2],[3] We report a patient with a novel de novo pathogenic SMC1A truncating variant.

   Case Report Top

A 3-year-old girl born to nonconsanguineous parents, with normal birth and motor development till 8 months of age, presented with multiple seizures starting at the age of 8 months. Initially, she had few brief generalized tonic, clonic (GTC) seizures. They were followed by flexor spasms involving head and upper extremity, with squirming of face. The spasms occurred every 10 seconds in clusters lasting for few hours, at irregular intervals. She also had multiple episodes of behavioural arrest with impaired awareness lasting for few seconds daily. She regressed developmentally after seizure onset.

On examination, she had short stature, microcephaly, coarse facies, bushy eyebrows with long eyelashes, broad depressed nasal bridge, short shallow philtrum, low set posteriorly rotated ears with flattened midface, hypertrichosis, and short hands [Figure 1]a, [Figure 1]b, [Figure 1]c. Her developmental quotient was 55, with autistic features, and did not have any receptive or expressive language. Her systemic examination was normal.
Figure 1: Phenotype and EEG study of the patient. Phenotype and EEG study of the patient: Facial appearance (a, b) and short hand (c) of the patient. First EEG (d) showing frequent generalized epileptic activity followed by suppression and subsequent EEG after starting ACTH (e) showing improved background and decreased epileptic activity

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Her first sleep EEG showed frequent generalised bursts of spike and wave complexes with background suppression [Figure 1]d suggestive of modified hypsarrhythmia. Audiometry, metabolic screening (TMS) and MRI were normal. We classified her seizures as focal and generalized seizures and epilepsy as epileptic and developmental encephalopathy.[4] We started her on ACTH which resulted in seizure reduction and improvement on EEG [Figure 1]e. Thereafter despite adding Topiramate, Levetiracetam, Vigabatrin and Valproate consecutively, seizure were only partially controlled. She achieved complete seizure freedom only after starting Modified Atkins Diet (MAD) along with Zonisamide and Valproic acid and remained seizure free for a year. Recently she had seizure recurrence with cluster of GTC seizures. She regained some of the lost mile stones during the seizure free period but continued to have developmental delay with maximum impairment in speech and communication.

In view of pharmacoresistent seizures, genetic test in form of a neurology panel was conducted at a commercial laboratory. A novel pathogenic heterozygous deletion in the SMC1A gene was identified by this focused next generation sequencing on the illumina (MiSeq and NextSeq) platform. The variant (c. 3305_3312del) was predicted to cause a frameshift and consequent premature termination of the protein (p.Asn1102ArgfsTer53) resulting in loss-of-function. Moreover, due to introduction of premature stop codon, this aberrant transcript would likely be targeted by nonsense mediated mRNA decay mechanism. The variant was considered to be de novo as both parents tested negative on Sanger sequencing.

   Discussion Top

The PCDH19 phenotype is a well-defined X linked inherited epilepsy syndrome. It is characterized by normal early development, infantile onset epilepsy with fever sensitive, convulsive seizure clusters at the onset and multiple seizure types later.[1] Some cases may show developmental stagnation or regression while rest (40%) develop normally.[2] Dysmorphism and congenital anomalies have not been reported in any.

Recently, 15 females with truncating pathogenic variants in SMC1A have been described with early infantile onset (median 4.5 months) drug resistant epilepsy. Generalized tonic, clonic seizures were predominant at onset. Multiple other generalized seizures like eyelid myoclonia, myoclonic, tonic, spasms, atypical absence, drop attacks and focal seizures including NCSE developed later. Majority of the seizures occurred in clusters and there was no fever sensitivity. All showed moderate to severe global developmental impairment prior to seizure onset and none developed expressive language. They had a distinct phenotype with short stature, microcephaly, flattened midface, short upturned nose and a shallow philtrum. Cardiac, vertebral and palatal anomalies were seen in few.[2],[3]

Missense variants and small in frame deletions in SMC1A present with non-classic phenotype of CdLS. It is characterized by fuller eyebrows, rounder face and less prominent shortening of the nasal bridge with partial epilepsy amenable to standard therapy (45%) and mild cognitive delay.[5]

Our patient showed dysmorphisms, developmental impairment and epilepsy similar to previously described cases with pathogenic SMC1A truncating variants but did not have any congenital anomalies [Table 1]. She had generalized tonic, clonic seizures only at onset and at the time of recurrence but her predominant seizure type was epileptic spasms, which has been described only in 3 cases so far. As reported, her seizures were resistant to multiple AEDs, but she achieved seizure freedom with normalization of EEG on a combination of MAD and drugs. A similar response to Ketogenic Diet (KD) has been previously described in 2 cases.[2]
Table 1: Comparison of our patient with previously reported cases and differentials

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The MAD is a less restrictive alternative to the traditional ketogenic diet. It is started on an outpatient basis without a fast and well tolerated as it allows unlimited protein and fat, without restricting calories or fluids.[6] In resource constraint settings of a developing country like India, it can be easily used with limited dietician support, as it does not require tedious calculations.[7] A significant response has been documented in infantile spasm refractory to antiepileptics and steroids.[8] No statistical significance has been demonstrated in the beneficial outcomes of classical KD and MAD even in symptomatic etiologies including genetic disorders.[9] Ours is the first reported case of pathogenic SMC1A truncating variant from India and the only one amongst these SMC1A in literature where MAD has been tried and found beneficial.

   Conclusion Top

Pathogenic truncating variants in SMC1A is an emerging X linked early onset epileptic and developmental encephalopathy. It should be considered as an important differential in females with severe developmental delay and drug resistant epilepsy in clusters, along with PCDH19 associated syndrome. We recommend early trial of MAD along with drugs in the management of epilepsy in these cases.


We thank the parents for giving us consent to share their child's details for scientific report. We would also like to thank Priya Karkera, pediatric nutritionist at our center for her guidance in patient's diet management.

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


Conflicts of interest

There are no conflicts of interest.

   References Top

Scheffer IE, Turner SJ, Dibbens LM, Bayly MA, Friend K, Hodgson B, et al. Epilepsy and mental retardation limited to females: An under-recognized disorder. Brain 2008;13:918-27.  Back to cited text no. 1
Symonds JD, Joss S, Metcalfe KA, Somarathi S, Cruden J, Devlin AM, et al. Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases. Epilepsia 2017;58:565-75.  Back to cited text no. 2
Jansen S, Kleefstra T, Willemsen MH, de Vries P, Pfundt R, Hehir-Kwa JY, et al. De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: Expanding the phenotypic spectrum. Clin Genet 2016;90:413-9.  Back to cited text no. 3
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512-21.  Back to cited text no. 4
Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gilelett PM, et al. Diagnosis and management of Cornelia de Lange syndrome: First international consensus statement. Nat Rev Genet 2018;19:649-66.  Back to cited text no. 5
Park EG, Lee J, Lee J. Use of the modified Atkins diet in intractable pediatric epilepsy. J Epilepsy Res 2018;8:20-6.  Back to cited text no. 6
Sharma S, Jain P. The modified atkins diet in refractory epilepsy. Epilepsy Res Treat 2014;2014:404202.  Back to cited text no. 7
Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet in infantile spasms refractory to first-line treatment. Seizure 2012;21:45-8.  Back to cited text no. 8
Riantarini I, Kim HD, Ko A, Kim SH, Kang HC, Lee JS, et al. Short- and long-term seizure-free outcomes of dietary treatment in infants according to etiology. Seizure 2019;71:100-4.  Back to cited text no. 9


  [Figure 1]

  [Table 1]


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