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Carbohydrate-deficient glycoprotein syndrome type I(CDG1A)

MedGen UID:
138111
Concept ID:
C0349653
Disease or Syndrome
Synonyms: Carbohydrate-deficient glycoprotein syndrome type 1A; Carbohydrate-deficient glycoprotein syndrome type 1A (formerly); CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE Ia; CDG 1A; CDG Ia; CDG1A; CDGS1a; Congenital disorder of glycosylation type 1A; CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia; Jaeken syndrome; Phosphomannomutase 2 deficiency; PMM deficiency; PMM2-CDG (CDG-Ia)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
SNOMED CT: Congenital disorder of glycosylation type Ia (459063003); Carbohydrate-deficient glycoprotein syndrome type I (277893002); CDG - Carbohydrate-deficient glycoprotein syndrome type I (277893002)
 
Gene: PMM2
Cytogenetic location: 16p13.2
OMIM: 212065

Definition

PMM2-CDG (CDG-Ia) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three stages: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three stages notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in siblings. In the infantile multisystem stage, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay; feeding problems, vomiting, and diarrhea with failure to thrive; and impaired growth. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia-intellectual disability stage, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk of deep venous thrombosis is present. [from GeneReviews]

Additional descriptions

From OMIM
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs (see, e.g., CDG2A, 212066) refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. CDG1A is the most common form of CDG and was the first to be characterized at the molecular level (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002). Matthijs et al. (1997) noted that Jaeken syndrome (CDG1A) is a genetic multisystem disorder characterized by defective glycosylation of glycoconjugates. It usually presents as a severe disorder in the neonatal period. There is a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced psychomotor retardation, as well as peripheral neuropathy, cerebellar hypoplasia, and retinitis pigmentosa. Patients show a peculiar distribution of subcutaneous fat, nipple retraction, and hypogonadism. There is a 20% lethality in the first year of life due to severe infections, liver insufficiency, or cardiomyopathy. Genetic Heterogeneity of Congenital Disorder of Glycosylation Type I Multiple forms of CDG type I have been identified; see CDG1B (602579) through CDG1X (615597). A congenital disorder of deglycosylation (CDDG; 615273), previously designated CDG1V, is caused by mutation in the NGLY1 gene (610661).  http://www.omim.org/entry/212065
From GHR
Congenital disorder of glycosylation type Ia (CDG-Ia), also known as phosphomannomutase 2 deficiency, is an inherited condition that affects many parts of the body. The type and severity of problems associated with CDG-Ia vary widely among affected individuals, sometimes even among members of the same family. Individuals with CDG-Ia typically develop signs and symptoms of the condition during infancy. Affected infants may have weak muscle tone (hypotonia), retracted (inverted) nipples, an abnormal distribution of fat, eyes that do not look in the same direction (strabismus), developmental delay, and a failure to gain weight and grow at the expected rate (failure to thrive). Infants with CDG-Ia also frequently have an underdeveloped cerebellum, which is the part of the brain that coordinates movement. Distinctive facial features are sometimes present in affected individuals, including a high forehead, a triangular face, large ears, and a thin upper lip. Children with CDG-Ia may also have elevated liver function tests, seizures, fluid around the heart (pericardial effusion), and blood clotting disorders. About 20 percent of affected infants do not survive the first year of life due to multiple organ failure. The most severe cases of CDG-Ia are characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Most babies with hydrops fetalis are stillborn or die soon after birth. People with CDG-Ia who survive infancy may have moderate intellectual disability, and some are unable to walk independently. Affected individuals may also experience stroke-like episodes that involve an extreme lack of energy (lethargy) and temporary paralysis. Recovery from these episodes usually occurs over a period of a few weeks to several months. During adolescence or adulthood, individuals with CDG-Ia have reduced sensation and weakness in their arms and legs (peripheral neuropathy), an abnormal curvature of the spine (kyphoscoliosis), impaired muscle coordination (ataxia), and joint deformities (contractures). Some affected individuals have an eye disorder called retinitis pigmentosa that causes vision loss. Females with CDG-Ia have hypergonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, females with CDG-Ia do not go through puberty. Affected males experience normal puberty but often have small testes.  http://ghr.nlm.nih.gov/condition/congenital-disorder-of-glycosylation-type-ia

Clinical features

Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
abnormal presence of protein in urine
Renal cyst
MedGen UID:
776573
Concept ID:
C2173677
Finding
A cyst is a fluid-filled sac. There are two types of kidney cysts. . Polycystic kidney disease (PKD) runs in families. In PKD, the cysts take the place of the normal tissue. They enlarge the kidneys and make them work poorly, leading to kidney failure. When PKD causes kidneys to fail - which usually happens after many years - people need dialysis or kidney transplantation. About half of people with the most common type of PKD end up with kidney failure. PKD also causes cysts in other parts of the body, such as the liver. . Symptoms of PKD include: -Pain in the back and lower sides. -Headaches. -Urinary tract infections. -Blood in the urine. Doctors diagnose PKD with imaging tests and family history. Treatments include medications, and, when people with PKD develop kidney failure, dialysis or kidney transplants. Acquired cystic kidney disease (ACKD) usually happens in people who are on dialysis. Unlike PKD, the kidneys are normal sized, and cysts do not form in other parts of the body. People with ACKD already have chronic kidney disease when they develop cysts. ACKD often has no symptoms. In most cases, the cysts are harmless and do not need treatment. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Nephrotic syndrome
MedGen UID:
504341
Concept ID:
CN000100
Finding
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Hypergonadotropic hypogonadism
MedGen UID:
425015
Concept ID:
CN000762
Finding
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Primary ovarian failure
MedGen UID:
504864
Concept ID:
CN001445
Finding
Malfunctioning of the ovaries such that a girl never begins menstruation.
Thin upper lip vermilion
MedGen UID:
507078
Concept ID:
CN000212
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Depressed nasal bridge
MedGen UID:
446656
Concept ID:
CN004681
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Retinitis pigmentosa
MedGen UID:
504473
Concept ID:
CN000477
Finding
Hereditary degeneration and atrophy of the retina.
Esotropia
MedGen UID:
504499
Concept ID:
CN000530
Finding
A form of strabismus with one or both eyes turned inward ('crossed').
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
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.
Polyneuropathy
MedGen UID:
504780
Concept ID:
CN001165
Finding
A generalized disorder of peripheral nerves.
Inverted nipples
MedGen UID:
505476
Concept ID:
CN002877
Finding
The presence of nipples that instead of pointing outward are retracted inwards.
Hypergonadotropic hypogonadism
MedGen UID:
425015
Concept ID:
CN000762
Finding
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Flexion contracture
MedGen UID:
504817
Concept ID:
CN001256
Finding
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Hepatic fibrosis
MedGen UID:
504827
Concept ID:
CN001276
Finding
The presence of `fibrosis` (MPATH:181) of the `liver` (FMA:7197) tissue.
Hepatic steatosis
MedGen UID:
427871
Concept ID:
CN001278
Finding
The presence of `steatosis` (MPATH:622) in the `liver` (FMA:7197).
Hepatomegaly
MedGen UID:
505165
Concept ID:
CN002031
Finding
Abnormally `increased size` (PATO:0000586) of the `liver` (FMA:7197).
Elevated hepatic transaminases
MedGen UID:
505403
Concept ID:
CN002632
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Cardiomyopathy
MedGen UID:
504883
Concept ID:
CN001491
Finding
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Pericardial effusion
MedGen UID:
504918
Concept ID:
CN001544
Finding
Accumulation of fluid within the pericardium.
Prolonged partial thromboplastin time
MedGen UID:
66815
Concept ID:
C0240671
Finding
An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Thrombocytosis
MedGen UID:
504993
Concept ID:
CN001712
Finding
Increased numbers of platelets in the peripheral blood.
Reduced factor XI activity
MedGen UID:
505010
Concept ID:
CN001745
Finding
Decreased activity of `coagulation factor XI` (PR:000007295). Factor XI, also known as plasma thromboplastin antecedent, is a serine proteinase that activates factor IX.
Reduced antithrombin III activity
MedGen UID:
505034
Concept ID:
CN001788
Finding
An `abnormality of coagulation` (HP:0001928) related to a `decreased concentration` (PATO:0001163) of `antithrombin-III` (PR:000003252).
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
abnormal presence of protein in urine
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduced serum albumin concentration
Hypocholesterolemia
MedGen UID:
505465
Concept ID:
CN002838
Finding
An decreased concentration of `cholesterol` (CHEBI:16113) in the `blood` (FMA:9670).
Type I transferrin isoform profile
MedGen UID:
500961
Concept ID:
CN003290
Finding
Abnormal transferrin isoform profile consistent with a type I congenital disorder of glycosylation. In the traditional nomenclature for congenital disorders of glycosylation, absence of entire glycans was designated type I, and loss of one or more monosaccharides as type II.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
A reduction in the strength of one or more muscles.
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.
Flexion contracture
MedGen UID:
504817
Concept ID:
CN001256
Finding
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Flexion contracture
MedGen UID:
504817
Concept ID:
CN001256
Finding
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews

Recent clinical studies

Etiology

Iourin O, Mattu TS, Mian N, Keir G, Winchester B, Dwek RA, Rudd PM
Glycoconj J 1996 Dec;13(6):1031-42. PMID: 8981095
Pavone L, Fiumara A, Barone R, Rizzo R, Buttitta P, Dobyns WB, Jaeken J
J Neurol 1996 Oct;243(10):700-5. PMID: 8923302
Fiumara A, Barone R, Buttitta P, Musso R, Pavone L, Nigro F, Jaeken J
Thromb Haemost 1996 Oct;76(4):502-4. PMID: 8902985
Stibler H, Holzbach U, Tengborn L, Kristiansson B
Blood Coagul Fibrinolysis 1996 Mar;7(2):118-26. PMID: 8735800

Diagnosis

Henry H, Froehlich F, Perret R, Tissot JD, Eilers-Messerli B, Lavanchy D, Dionisi-Vici C, Gonvers JJ, Bachmann C
Clin Chem 1999 Sep;45(9):1408-13. PMID: 10471642
Mizugishi K, Yamanaka K, Kuwajima K, Yuasa I, Shigemoto K, Kondo I
Brain Dev 1999 Jun;21(4):223-8. PMID: 10392743
Stibler H, Holzbach U, Kristiansson B
Scand J Clin Lab Invest 1998 Feb;58(1):55-61. PMID: 9516657
Iourin O, Mattu TS, Mian N, Keir G, Winchester B, Dwek RA, Rudd PM
Glycoconj J 1996 Dec;13(6):1031-42. PMID: 8981095
Matthijs G, Legius E, Schollen E, Vandenberk P, Jaeken J, Barone R, Fiumara A, Visser G, Lambert M, Cassiman JJ
Genomics 1996 Aug 1;35(3):597-9. doi: 10.1006/geno.1996.0404. PMID: 8812498

Therapy

Mayatepek E, Schröder M, Kohlmüller D, Bieger WP, Nützenadel W
Acta Paediatr 1997 Oct;86(10):1138-40. PMID: 9350901
Alton G, Kjaergaard S, Etchison JR, Skovby F, Freeze HH
Biochem Mol Med 1997 Apr;60(2):127-33. PMID: 9169093

Prognosis

Worthington S, Arbuckle S, Nelson P, Carey W, Lipson A, Fagan E
J Paediatr Child Health 1997 Dec;33(6):531-4. PMID: 9484687

Clinical prediction guides

Beccari T, Mancuso F, Costanzi E, Tassi C, Barone R, Fiumara A, Orlacchio A, Aisa MC, Orlacchio A
Clin Chim Acta 2000 Dec;302(1-2):125-32. PMID: 11074069
Körner C, Lehle L, von Figura K
Glycobiology 1998 Feb;8(2):165-71. PMID: 9451026
Alton G, Kjaergaard S, Etchison JR, Skovby F, Freeze HH
Biochem Mol Med 1997 Apr;60(2):127-33. PMID: 9169093
Matthijs G, Legius E, Schollen E, Vandenberk P, Jaeken J, Barone R, Fiumara A, Visser G, Lambert M, Cassiman JJ
Genomics 1996 Aug 1;35(3):597-9. doi: 10.1006/geno.1996.0404. PMID: 8812498
Martinsson T, Bjursell C, Stibler H, Kristiansson B, Skovby F, Jaeken J, Blennow G, Strömme P, Hanefeld F, Wahlström J
Hum Mol Genet 1994 Nov;3(11):2037-42. PMID: 7874123

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