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Creatine deficiency, X-linked(CCDS1)

MedGen UID:
337451
Concept ID:
C1845862
Disease or Syndrome
Synonyms: CCDS1; CEREBRAL CREATINE DEFICIENCY SYNDROME 1; Creatine Deficiency Syndromes; CREATINE TRANSPORTER DEFECT; Mental retardation , X-linked with seizures, short stature and midface hypoplasia; Mental retardation , X-linked, with creatine transport deficiency; SLC6A8-Related Creatine Transporter Deficiency; X-linked creatine deficiency syndrome; X-linked creatine transporter deficiency
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
425042
Concept ID:
CN001297
Genetic Function
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
SNOMED CT: X-linked creatine deficiency syndrome (698290008); SLC6A8 related creatine transporter deficiency (698290008); X-linked creatine deficiency (698290008); Creatine transporter deficiency (698290008)
 
Gene: SLC6A8
Cytogenetic location: Xq28
OMIM®: 300352
Orphanet: ORPHA52503

Disease characteristics

Excerpted from the GeneReview: Creatine Deficiency Syndromes
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT or GATM) deficiency, and the creatine transporter (SLC6A8) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; a significant proportion have pyramidal/extrapyramidal findings. Onset is between ages three months and three years. Only seven individuals with AGAT deficiency have been reported. The phenotype of SLC6A8 deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, and behavior disorder; age at diagnosis ranges from two to 66 years. Females heterozygous for SLC6A8 deficiency may have learning and behavior problems. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Saadet Mercimek-Mahmutoglu  |  Sylvia Stöckler-Ipsiroglu  |  Gajja S Salomons   view full author information

Additional descriptions

From OMIM
Cerebral creatine deficiency syndrome-1 is an X-linked disorder of creatine (Cr) transport characterized by mental retardation, severe speech delay, behavioral abnormalities, and seizures. It has a prevalence of 0.3 to 3.5% in males. Carrier females may show mild neuropsychologic impairment (summary by van de Kamp et al., 2011). Genetic Heterogeneity of Cerebral Creatine Deficiency Syndrome See also CCDS2 (612736), caused by mutation in the GAMT gene (601240) on chromosome 19p13, and CCDS3 (612718), caused by mutation in the AGAT gene (GATM; 602360) on chromosome 15q15.  http://www.omim.org/entry/300352
From GHR
X-linked creatine deficiency is an inherited disorder that primarily affects the brain. People with this disorder have intellectual disability, which can range from mild to severe, and delayed speech development. Some affected individuals develop behavioral disorders such as attention deficit hyperactivity disorder or autistic behaviors that affect communication and social interaction. They may also experience seizures. Children with X-linked creatine deficiency may experience slow growth and exhibit delayed development of motor skills such as sitting and walking. Affected individuals tend to tire easily. A small number of people with X-linked creatine deficiency have additional signs and symptoms including abnormal heart rhythms, an unusually small head (microcephaly), or distinctive facial features such as a broad forehead and a flat or sunken appearance of the middle of the face (midface hypoplasia).  http://ghr.nlm.nih.gov/condition/x-linked-creatine-deficiency

Clinical features

Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Sign or Symptom
Slower than normal rate of weight increase.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
Decreased body weight
MedGen UID:
505609
Concept ID:
CN003826
Finding
Mask-like facies
MedGen UID:
140860
Concept ID:
C0424448
Finding
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Narrow face
MedGen UID:
373334
Concept ID:
C1837463
Finding
Microcephaly
MedGen UID:
337454
Concept ID:
C1845868
Finding
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Finding
Broad forehead
MedGen UID:
383676
Concept ID:
C1855408
Finding
Open mouth
MedGen UID:
346627
Concept ID:
C1857628
Finding
Malar flattening
MedGen UID:
347814
Concept ID:
C1859168
Finding
Myopathic facies
MedGen UID:
382494
Concept ID:
C2674980
Finding
Mandibular prognathia
MedGen UID:
427817
Concept ID:
CN000285
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Cheekbone underdevelopment
MedGen UID:
430039
Concept ID:
CN009495
Finding
Underdevelopment of the zygomatic bone. That is, a reduction in size of the zygomatic process of the temporal bone of the skull, which forms the middle and lateral inferior orbital margin.
Ptosis
MedGen UID:
504471
Concept ID:
CN000475
Finding
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Hypermetropia
MedGen UID:
504484
Concept ID:
CN000506
Finding
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.
Exotropia
MedGen UID:
504505
Concept ID:
CN000542
Finding
A form of strabismus with one or both eyes deviated outward.
Underfolded superior helices
MedGen UID:
501043
Concept ID:
CN007552
Finding
A condition in which the superior portion of the helix is folded over to a lesser degree than normal.
Hypertonia
MedGen UID:
115988
Concept ID:
C0235396
Finding
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Sign or Symptom
A finding referring to walking difficulties.
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Impaired social interactions
MedGen UID:
333406
Concept ID:
C1839794
Finding
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Poor hand-eye coordination
MedGen UID:
375756
Concept ID:
C1845864
Finding
Microcephaly
MedGen UID:
337454
Concept ID:
C1845868
Finding
Hypoplasia of the corpus callosum
MedGen UID:
342925
Concept ID:
C1853617
Finding
Cognitive impairment
MedGen UID:
383844
Concept ID:
C1856145
Finding
Incoordination
MedGen UID:
351047
Concept ID:
C1864113
Finding
Seizures
MedGen UID:
409523
Concept ID:
C1959629
Finding
Autism
MedGen UID:
504569
Concept ID:
CN000674
Finding
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication, and by restricted and repetitive behavior. Autism begins in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual (DSM-IV).
Aggressive behavior
MedGen UID:
504570
Concept ID:
CN000675
Finding
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Stereotypic behavior
MedGen UID:
427832
Concept ID:
CN000689
Finding
A repetitive behaviour that does not serve an observable goal. In general the movements are not aimed at the environment, but at the person itself. Stereotypical behaviour is seen especially in children with sensory, intellectual and/or cognitive handicaps.
Delayed speech and language development
MedGen UID:
504583
Concept ID:
CN000706
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Spasticity
MedGen UID:
504771
Concept ID:
CN001152
Finding
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Global developmental delay
MedGen UID:
504774
Concept ID:
CN001157
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Motor delay
MedGen UID:
504779
Concept ID:
CN001164
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Dystonia
MedGen UID:
504804
Concept ID:
CN001220
Finding
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Neurological speech impairment
MedGen UID:
446437
Concept ID:
CN001964
Finding
Aganglionic megacolon
MedGen UID:
505171
Concept ID:
CN002042
Finding
An abnormality resulting from a lack of intestinal ganglion cells (i.e., an aganglionic section of bowel) that results in bowel obstruction with enlargement of the colon.
Attention deficit hyperactivity disorder
MedGen UID:
506017
Concept ID:
CN006126
Finding
Attention deficit hyperactivity disorder (ADHD) manifests at age 2-3 years or by first grade at the latest. The main symptoms are distractibility, impulsivity, hyperactivity, and often trouble organizing tasks and projects, difficulty going to sleep, and social problems from being aggressive, loud, or impatient.
Abnormality of movement
MedGen UID:
506445
Concept ID:
CN116921
Finding
An abnormality of movement with a neurological basis characterized by changes in coordination and speed of voluntary movements.
Microcephaly
MedGen UID:
337454
Concept ID:
C1845868
Finding
Malar flattening
MedGen UID:
347814
Concept ID:
C1859168
Finding
Mandibular prognathia
MedGen UID:
427817
Concept ID:
CN000285
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Joint hypermobility
MedGen UID:
504821
Concept ID:
CN001265
Finding
The ability of a joint to move beyond its normal range of motion.
Cheekbone underdevelopment
MedGen UID:
430039
Concept ID:
CN009495
Finding
Underdevelopment of the zygomatic bone. That is, a reduction in size of the zygomatic process of the temporal bone of the skull, which forms the middle and lateral inferior orbital margin.
Constipation
MedGen UID:
368096
Concept ID:
C1963087
Finding
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Vomiting
MedGen UID:
776588
Concept ID:
C2712332
Finding
Aganglionic megacolon
MedGen UID:
505171
Concept ID:
CN002042
Finding
An abnormality resulting from a lack of intestinal ganglion cells (i.e., an aganglionic section of bowel) that results in bowel obstruction with enlargement of the colon.
Ileus
MedGen UID:
505288
Concept ID:
CN002357
Finding
Acute obstruction of the intestines preventing passage of the contents of the intestines.
Intestinal obstruction
MedGen UID:
505771
Concept ID:
CN004620
Finding
Blockage or impairment of the normal flow of the contents of the intestine towards the anal canal.
Cutis laxa
MedGen UID:
504669
Concept ID:
CN000911
Finding
Wrinkled, redundant, inelastic and sagging skin.
Abnormality of metabolism/homeostasis
MedGen UID:
446429
Concept ID:
CN001754
Finding
Hypertonia
MedGen UID:
115988
Concept ID:
C0235396
Finding
Neonatal hypotonia
MedGen UID:
331807
Concept ID:
C1834679
Finding
Muscular hypotonia
MedGen UID:
504768
Concept ID:
CN001147
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Spasticity
MedGen UID:
504771
Concept ID:
CN001152
Finding
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Pes cavus
MedGen UID:
425071
Concept ID:
CN001601
Finding
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.

Term Hierarchy

Recent clinical studies

Etiology

Kato H, Miyake F, Shimbo H, Ohya M, Sugawara H, Aida N, Anzai R, Takagi M, Okuda M, Takano K, Wada T, Iai M, Yamashita S, Osaka H
Brain Dev 2014 Aug;36(7):630-3. Epub 2013 Sep 14 doi: 10.1016/j.braindev.2013.08.004. [Epub ahead of print] PMID: 24045174
Comeaux MS, Wang J, Wang G, Kleppe S, Zhang VW, Schmitt ES, Craigen WJ, Renaud D, Sun Q, Wong LJ
Mol Genet Metab 2013 Jul;109(3):260-8. Epub 2013 Apr 17 doi: 10.1016/j.ymgme.2013.04.006. [Epub ahead of print] PMID: 23660394
van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca MA, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer HE, Hofstede F, Johnson D, Kant SG, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit JA, Monteiro JP, Munnich A, Muntau AC, Nassogne MC, Osaka H, Ounap K, Pinard JM, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz CE, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink MM, Pouwels PJ, Errami A, van der Knaap MS, Jakobs C, Mancini GM, Salomons GS
J Med Genet 2013 Jul;50(7):463-72. Epub 2013 May 3 doi: 10.1136/jmedgenet-2013-101658. [Epub ahead of print] PMID: 23644449

Diagnosis

Kato H, Miyake F, Shimbo H, Ohya M, Sugawara H, Aida N, Anzai R, Takagi M, Okuda M, Takano K, Wada T, Iai M, Yamashita S, Osaka H
Brain Dev 2014 Aug;36(7):630-3. Epub 2013 Sep 14 doi: 10.1016/j.braindev.2013.08.004. [Epub ahead of print] PMID: 24045174
Yu H, van Karnebeek C, Sinclair G, Hill A, Cui H, Zhang VW, Wong LJ
Mol Genet Metab 2013 Dec;110(4):465-71. Epub 2013 Oct 4 doi: 10.1016/j.ymgme.2013.09.018. [Epub ahead of print] PMID: 24140398
Comeaux MS, Wang J, Wang G, Kleppe S, Zhang VW, Schmitt ES, Craigen WJ, Renaud D, Sun Q, Wong LJ
Mol Genet Metab 2013 Jul;109(3):260-8. Epub 2013 Apr 17 doi: 10.1016/j.ymgme.2013.04.006. [Epub ahead of print] PMID: 23660394
van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca MA, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer HE, Hofstede F, Johnson D, Kant SG, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit JA, Monteiro JP, Munnich A, Muntau AC, Nassogne MC, Osaka H, Ounap K, Pinard JM, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz CE, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink MM, Pouwels PJ, Errami A, van der Knaap MS, Jakobs C, Mancini GM, Salomons GS
J Med Genet 2013 Jul;50(7):463-72. Epub 2013 May 3 doi: 10.1136/jmedgenet-2013-101658. [Epub ahead of print] PMID: 23644449
Wada T, Shimbo H, Osaka H
Amino Acids 2012 Aug;43(2):993-7. Epub 2011 Nov 13 doi: 10.1007/s00726-011-1146-1. [Epub ahead of print] PMID: 22080216

Prognosis

van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grünewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca MA, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer HE, Hofstede F, Johnson D, Kant SG, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit JA, Monteiro JP, Munnich A, Muntau AC, Nassogne MC, Osaka H, Ounap K, Pinard JM, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz CE, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink MM, Pouwels PJ, Errami A, van der Knaap MS, Jakobs C, Mancini GM, Salomons GS
J Med Genet 2013 Jul;50(7):463-72. Epub 2013 May 3 doi: 10.1136/jmedgenet-2013-101658. [Epub ahead of print] PMID: 23644449
Zhang Z, Witham S, Petukh M, Moroy G, Miteva M, Ikeguchi Y, Alexov E
J Am Med Inform Assoc 2013 Jul-Aug;20(4):643-51. Epub 2013 Feb 13 doi: 10.1136/amiajnl-2012-001505. [Epub ahead of print] PMID: 23408511Free PMC Article
Betsalel OT, Rosenberg EH, Almeida LS, Kleefstra T, Schwartz CE, Valayannopoulos V, Abdul-Rahman O, Poplawski N, Vilarinho L, Wolf P, den Dunnen JT, Jakobs C, Salomons GS
Eur J Hum Genet 2011 Jan;19(1):56-63. Epub 2010 Aug 18 doi: 10.1038/ejhg.2010.134. [Epub ahead of print] PMID: 20717164Free PMC Article
Puusepp H, Kall K, Salomons GS, Talvik I, Männamaa M, Rein R, Jakobs C, Õunap K
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S5-11. PMID: 24137762

Clinical prediction guides

Zhang Z, Witham S, Petukh M, Moroy G, Miteva M, Ikeguchi Y, Alexov E
J Am Med Inform Assoc 2013 Jul-Aug;20(4):643-51. Epub 2013 Feb 13 doi: 10.1136/amiajnl-2012-001505. [Epub ahead of print] PMID: 23408511Free PMC Article
Betsalel OT, Rosenberg EH, Almeida LS, Kleefstra T, Schwartz CE, Valayannopoulos V, Abdul-Rahman O, Poplawski N, Vilarinho L, Wolf P, den Dunnen JT, Jakobs C, Salomons GS
Eur J Hum Genet 2011 Jan;19(1):56-63. Epub 2010 Aug 18 doi: 10.1038/ejhg.2010.134. [Epub ahead of print] PMID: 20717164Free PMC Article
Puusepp H, Kall K, Salomons GS, Talvik I, Männamaa M, Rein R, Jakobs C, Õunap K
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S5-11. PMID: 24137762

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