Disorder
MASD syndrome

Clinical Characteristics

General description (for patients):

KPTN-related syndrome is an inherited condition characterised by macrocephaly (large head size), developmental delay, intellectual disability and behavioural problems, with some individuals developing seizures. All individuals have intellectual disability, although this can range from mild to severe. Developmental delay is seen in most individuals with delay in speech development or age at crawling/walking. Over 50% will develop seizures and the risk of this increases with age, seizures are usually of two types: generalised tonic-clonic (grand mal) or absence and some individuals display both types of seizure. Individuals with KPTN-related syndrome have a larger than average head size, most are significantly increased, called macrocephaly. All individuals show behavioural problems, which can include anxiety, autistic features, repetitive behaviours and hyperactivity. Most affected individuals have recognisable facial features, for example a prominent forehead.

Medical description (for healthcare providers):

Biallelic pathogenic variants in KPTN result in a neurodevelopmental disorder characterised by variable intellectual disability (mild to severe) with associated variable delay in speech and motor milestones, a few individuals are non-verbal. Childhood hypotonia is common and macrocephaly (SD>+2) occurs in most affected individuals, although this usually develops postnatally. There is an increased risk of seizures with age and most individuals develop generalised tonic-clonic or absence seizures. Brain imaging shows generally enlarged brain size, although there are no recognisable specific abnormalities except mild ventriculomegaly.

Individuals with KPTN-related syndrome have recognisable facial dysmorphology, including features of frontal bossing, prominent chin, scaphocephaly, hypertelorism and downslanting palpebral fissures. Other dysmorphic features include 5^th finger clinodactyly and fetal finger pads. Other notable features include recurrent infections, hepatosplenomegaly and strabismus. A behavioural phenotype is recognisable in individuals with KPTN-related syndrome, including anxiety, which can include panic attacks and phobias, autistic features, stereotypies, repetitive speech and hyperactivity.

Genetics:

KPTN-related syndrome is an autosomal recessive condition caused by biallelic mutation in KPTN on chromosome 19. This gene encodes kaptin, a poorly characterised protein that may play a regulatory role in actin polymerisation and forms a complex with 3 other molecules called KICSTOR that has downstream effects on the mTOR pathway.

To date 25 patients with KPTN-related syndrome have been identified worldwide. Many of these individuals are from the Anabaptist community in the US, in whom the condition was first identified and two common variants have been reported: (NM_007059.3); c.776C>A; p.Ser259* and c.714_731 dup; p.Met241_Gln246dup. The latter inframe duplication variant has now been identified more widely as a founder variant in the European population, and several more variants within KPTN have subsequently been identified in other populations.

Management:

There is no known treatment for this disorder. Currently management is largely supportive, including physiotherapy and speech therapy to help with delay in development. Management of seizures is important with good seizure control, as this is an important cause of morbidity and mortality in KPTN-related syndrome, although there is currently no specific guidance on antiepileptic management.

As KPTN-related syndrome has been linked to hyperactivation of the mTOR pathway, it is hoped that mTOR inhibitors, for example rapamycin, that have been effective in other conditions like tuberose sclerosis, that arise from the hyperactivation of the mTOR pathway may also be effective in this KPTN-related syndrome. Trials of mTOR inhibitors in mouse models of the condition are currently underway and provide promise that a treatment option may be available in the future.

Prognosis:

KPTN-related syndrome is a macrocephalic neurodevelopmental disorder, with onset of symptoms from infancy. Prognosis is similar to other individuals with mild to severe intellectual disability and the oldest individual known to have KPTN-related syndrome is currently 56 years old. There is an increased risk of seizure development with age, and this is an important cause of morbidity and mortality in this condition. A single individual with refractory seizures died from status epilepticus at the age of 9 years.

References:

1. Baple EL, Maroofian R, Chioza BA, Izadi M, Cross HE, Al-Turki S, et al. Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am J Hum Genet. 2014;94(1):87-94. Epub 2013/11/14. doi: 10.1016/j.ajhg.2013.10.001. PubMed PMID: 24239382; PubMed Central PMCID: PMCPMC3882725.
2. Pajusalu S, Reimand T, Ounap K. Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. American journal of medical genetics Part A. 2015;167a(8):1913-5. Epub 2015/04/08. doi: 10.1002/ajmg.a.37105
3. Thiffault I, Atherton A, Heese BA, Abdelmoity A, Pawar K, Farrow E, et al. Pathogenic variants in KPTN gene identified by Clinical Whole Whole-Genome Sequencing. Journal of Genetic and Hereditary Case Studies. 2018;1(1):1-6.
4. Wolfson RL, Chantranupong L, Wyant GA, Gu X, Orozco JM, Shen K, et al. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature. 2017;543(7645):438-42. Epub 2017/02/15. doi: 10.1038/nature21423. PubMed PMID: 28199306; PubMed Central PMCID: PMCPMC5360989.