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Inborn glycerol kinase deficiency(GKD)

MedGen UID:
82803
Concept ID:
C0268418
Disease or Syndrome
Synonyms: Deficiency of glycerol kinase; GK deficiency; GK1 deficiency; Glycerol Kinase Deficiency; Hyperglycerolemia
SNOMED CT: Deficiency of glycerol kinase (124322002); Glycerol kinase deficiency (124322002); GKD - Glycerol kinase deficiency (124322002); GK1 deficiency (124322002); Familial hyperglycerolemia (124322002); Hyperglycerolemia (124322002)
 
Gene (location): GK (Xp21.2)
 
HPO: HP:0040302
Monarch Initiative: MONDO:0010613
OMIM®: 307030
Orphanet: ORPHA308993

Disease characteristics

Excerpted from the GeneReview: NR0B1-Related Adrenal Hypoplasia Congenita
NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD. [from GeneReviews]
Authors:
John C Achermann  |  Eric J Vilain   view full author information

Additional description

From OMIM
Francke et al. (1987) noted that there are 3 clinically distinct forms of glycerol kinase deficiency: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay, and those with the adult form have no symptoms and are often detected fortuitously. The infantile form of GK deficiency, or the 'GK complex,' results from the Xp21 contiguous gene deletion syndrome (300679) with congenital adrenal hypoplasia (300200) and/or Duchenne muscular dystrophy (DMD; 310200), whereas the juvenile and adult forms have isolated GK deficiency (Walker et al., 1996).  http://www.omim.org/entry/307030

Clinical features

From HPO
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Increased urinary glycerol
MedGen UID:
388667
Concept ID:
C2673558
Finding
An increased concentration of glycerol in the urine.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Nausea
MedGen UID:
10196
Concept ID:
C0027497
Sign or Symptom
A sensation of unease in the stomach together with an urge to vomit.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Loss of consciousness
MedGen UID:
52915
Concept ID:
C0041657
Finding
Loss of alertness and orientation to place and time.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Pathologic fracture
MedGen UID:
42095
Concept ID:
C0016663
Pathologic Function
A pathologic fracture occurs when a bone breaks in an area that is weakened secondarily to another disease process such as tumor, infection, and certain inherited bone disorders. A pathologic fracture can occur without a degree of trauma required to cause fracture in healthy bone.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Disease or Syndrome
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Chronic pancreatitis
MedGen UID:
101753
Concept ID:
C0149521
Disease or Syndrome
A chronic form of pancreatitis.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Ketoacidosis
MedGen UID:
67434
Concept ID:
C0220982
Disease or Syndrome
Acidosis resulting from accumulation of ketone bodies.
Inborn glycerol kinase deficiency
MedGen UID:
82803
Concept ID:
C0268418
Disease or Syndrome
NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Reduced glycerol kinase activity in cultured fibroblasts
MedGen UID:
1050791
Concept ID:
CN375682
Finding
Acitivity of glycerol kinase (EC 2.7.1.30) below the lower limit of normal in cultured fibroblasts.
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Anatomical Abnormality
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.
Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.
Adrenocortical hypoplasia
MedGen UID:
870278
Concept ID:
C4024719
Anatomical Abnormality
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Conditions with this feature

Inborn glycerol kinase deficiency
MedGen UID:
82803
Concept ID:
C0268418
Disease or Syndrome
NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.

Professional guidelines

PubMed

Pillai A, Warren G, Gunathilake W, Idris I
Diabetes Technol Ther 2011 Sep;13(9):945-9. Epub 2011 Jun 29 doi: 10.1089/dia.2011.0005. PMID: 21714680

Recent clinical studies

Etiology

Erdöl Ş, Sağlam H
J Clin Res Pediatr Endocrinol 2016 Sep 1;8(3):330-3. Epub 2016 Apr 18 doi: 10.4274/jcrpe.2288. PMID: 27086477Free PMC Article
Backes JM, Dayspring TD, Hoefner DM, Moriarty PM
BMJ Case Rep 2015 Oct 14;2015 doi: 10.1136/bcr-2015-210788. PMID: 26468219Free PMC Article
Soltani A, Argani H, Soleimani F, Rahimipour H, Akbarzadeh-Baghban A, Azizi T, Kazerouni F, Farshchian F
Exp Clin Transplant 2015 Dec;13(6):524-8. Epub 2015 Jun 15 doi: 10.6002/ect.2014.0221. PMID: 26086712
Grimnes G, Figenschau Y, Almås B, Jorde R
Diabetes 2011 Nov;60(11):2748-57. Epub 2011 Sep 12 doi: 10.2337/db11-0650. PMID: 21911741Free PMC Article
Pillai A, Warren G, Gunathilake W, Idris I
Diabetes Technol Ther 2011 Sep;13(9):945-9. Epub 2011 Jun 29 doi: 10.1089/dia.2011.0005. PMID: 21714680

Diagnosis

Montoya-Williams D, Mowitz M
Pediatrics 2017 Jul;140(1) doi: 10.1542/peds.2016-1479. PMID: 28759390
Erdöl Ş, Sağlam H
J Clin Res Pediatr Endocrinol 2016 Sep 1;8(3):330-3. Epub 2016 Apr 18 doi: 10.4274/jcrpe.2288. PMID: 27086477Free PMC Article
Arrobas-Velilla T, Mondéjar-García R, Gómez-Gerique JA, Cañizares Díaz I, Cruz Mengibar MC, Orive de Diego A, Fabiani-Romero F
Clin Investig Arterioscler 2013 Jul-Aug;25(3):123-6. Epub 2013 Jul 19 doi: 10.1016/j.arteri.2013.05.005. PMID: 23877006
Wikiera B, Jakubiak A, Zimowski J, Noczyńska A, Smigiel R
Pediatr Endocrinol Diabetes Metab 2012;18(4):153-7. PMID: 23739620
Sjarif DR, Ploos van Amstel JK, Duran M, Beemer FA, Poll-The BT
J Inherit Metab Dis 2000 Sep;23(6):529-47. doi: 10.1023/a:1005660826652. PMID: 11032329

Therapy

Montoya-Williams D, Mowitz M
Pediatrics 2017 Jul;140(1) doi: 10.1542/peds.2016-1479. PMID: 28759390
Kramer CK, Borgoño CA, Van Nostrand P, Retnakaran R, Zinman B
Diabetes Care 2014 Apr;37(4):1076-82. Epub 2013 Nov 15 doi: 10.2337/dc13-2339. PMID: 24241790
Arrobas-Velilla T, Mondéjar-García R, Gómez-Gerique JA, Cañizares Díaz I, Cruz Mengibar MC, Orive de Diego A, Fabiani-Romero F
Clin Investig Arterioscler 2013 Jul-Aug;25(3):123-6. Epub 2013 Jul 19 doi: 10.1016/j.arteri.2013.05.005. PMID: 23877006
Grimnes G, Figenschau Y, Almås B, Jorde R
Diabetes 2011 Nov;60(11):2748-57. Epub 2011 Sep 12 doi: 10.2337/db11-0650. PMID: 21911741Free PMC Article
Seltzer WK, Firminger H, Klein J, Pike A, Fennessey P, McCabe ER
Biochem Med 1985 Apr;33(2):189-99. doi: 10.1016/0006-2944(85)90027-4. PMID: 2988520

Prognosis

Backes JM, Dayspring TD, Hoefner DM, Moriarty PM
BMJ Case Rep 2015 Oct 14;2015 doi: 10.1136/bcr-2015-210788. PMID: 26468219Free PMC Article
Wibmer T, Otto J, Parhofer KG, Otto C
Exp Clin Endocrinol Diabetes 2005 Jul;113(7):396-403. doi: 10.1055/s-2005-865723. PMID: 16025401

Clinical prediction guides

Korkut S, Baştuğ O, Raygada M, Hatipoğlu N, Kurtoğlu S, Kendirci M, Lyssikatos C, Stratakis CA
J Clin Res Pediatr Endocrinol 2016 Dec 1;8(4):468-471. Epub 2016 Apr 18 doi: 10.4274/jcrpe.2539. PMID: 27087023Free PMC Article
Lu Z, Li Y, Samuvel DJ, Jin J, Zhang X, Lopes-Virella MF, Huang Y
Immunology 2013 Nov;140(3):301-13. doi: 10.1111/imm.12138. PMID: 23800176Free PMC Article
Grimnes G, Figenschau Y, Almås B, Jorde R
Diabetes 2011 Nov;60(11):2748-57. Epub 2011 Sep 12 doi: 10.2337/db11-0650. PMID: 21911741Free PMC Article
Pillai A, Warren G, Gunathilake W, Idris I
Diabetes Technol Ther 2011 Sep;13(9):945-9. Epub 2011 Jun 29 doi: 10.1089/dia.2011.0005. PMID: 21714680
Zhang YH, Huang BL, Jialal I, Northrup H, McCabe ER, Dipple KM
Pediatr Res 2006 Apr;59(4 Pt 1):590-2. doi: 10.1203/01.pdr.0000203092.83074.eb. PMID: 16549535

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