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Deficiency of hydroxymethylglutaryl-CoA lyase(HMGCLD)

MedGen UID:
78692
Concept ID:
C0268601
Disease or Syndrome
Synonyms: 3-hydroxy-3-methylglutaric aciduria; 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; 3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase Deficiency; Defect in leucine metabolism; HL deficiency; HMG CoA lyase deficiency; HMGCL DEFICIENCY; HMGCLD; Hydroxymethylglutaric aciduria
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Deficiency of hydroxymethylglutaryl-CoA lyase (124611007); 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (124611007); HMG-CoA lyase deficiency (124611007)
 
Gene (location): HMGCL (1p36.11)
OMIM®: 246450

Definition

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988). [from OMIM]

Additional description

From GHR
3-hydroxy-3-methylglutaryl-CoA lyase deficiency (also known as HMG-CoA lyase deficiency) is an uncommon inherited disorder in which the body cannot process a particular protein building block (amino acid) called leucine. Additionally, the disorder prevents the body from making ketones, which are compounds that are used for energy during periods without food (fasting).The signs and symptoms of HMG-CoA lyase deficiency usually appear within the first year of life. The condition causes episodes of vomiting, diarrhea, dehydration, extreme tiredness (lethargy), and weak muscle tone (hypotonia). During an episode, blood sugar levels can become dangerously low (hypoglycemia), and a buildup of harmful compounds can cause the blood to become too acidic (metabolic acidosis). If untreated, the disorder can lead to breathing problems, convulsions, coma, and death. Episodes are often triggered by an infection, fasting, strenuous exercise, or other types of stress.HMG-CoA lyase deficiency is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.  https://ghr.nlm.nih.gov/condition/3-hydroxy-3-methylglutaryl-coa-lyase-deficiency

Clinical features

From HPO
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies in the urine.
Glutaric aciduria
MedGen UID:
75695
Concept ID:
C0268594
Disease or Syndrome
An increased concentration of glutaric acid in the urine.
3-Methylglutaric aciduria
MedGen UID:
463302
Concept ID:
C3151952
Finding
Increased level of 3-hydroxy-3-methylglutaric acid in urine
MedGen UID:
1647053
Concept ID:
C4703617
Finding
Increased level of hippuric acid in urine
MedGen UID:
1640306
Concept ID:
C4703632
Finding
An increase in the level of hippuric acid in the urine.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
A profound state of unconsciousness associated with depressed cerebral activity from which the individual cannot be aroused. Coma generally occurs when there is dysfunction or injury involving both cerebral hemispheres or the brain stem RETICULAR FORMATION.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
An emotional state of indifference characterized by a lack of interest or concern.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Pschomotor retardation
MedGen UID:
98405
Concept ID:
C0424230
Finding
Abnormally slow physical movement.
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.
Excessive daytime somnolence
MedGen UID:
151959
Concept ID:
C0694563
Disease or Syndrome
A state of abnormally strong desire for sleep during the daytime.
Abnormality of the cerebral white matter
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Decreased prothrombin time
MedGen UID:
154375
Concept ID:
C0580413
Finding
Abnormally short time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula: INR is equal to Patient PT divided by Control PT.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
A condition characterized by an abnormally high body temperature. In a hyperthermic state, the hypothalamic set-point is normal but body temperature increases and overrides the ability to lose heat, resulting from exogenous heat exposure or endogenous heat production.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies in the urine.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Acid accumulation or depletion of base in the body due to buildup of metabolic acids.
Hyperammonemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
A laboratory test result demonstrating an increased concentration of ammonia in the blood.
Glutaric aciduria
MedGen UID:
75695
Concept ID:
C0268594
Disease or Syndrome
An increased concentration of glutaric acid in the urine.
Hyperuricemia
MedGen UID:
149260
Concept ID:
C0740394
Disease or Syndrome
An abnormally high level of uric acid in the blood.
Decreased plasma carnitine
MedGen UID:
222973
Concept ID:
C1142132
Finding
A decreased concentration of carnitine in the blood.
3-Methylglutaric aciduria
MedGen UID:
463302
Concept ID:
C3151952
Finding
Increased level of 3-hydroxy-3-methylglutaric acid in urine
MedGen UID:
1647053
Concept ID:
C4703617
Finding
Increased level of hippuric acid in urine
MedGen UID:
1640306
Concept ID:
C4703632
Finding
An increase in the level of hippuric acid in the urine.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Pallor
MedGen UID:
10547
Concept ID:
C0030232
Finding
A clinical manifestation consisting of an unnatural paleness of the skin.
Decreased plasma carnitine
MedGen UID:
222973
Concept ID:
C1142132
Finding
A decreased concentration of carnitine in the blood.
3-Methylglutaric aciduria
MedGen UID:
463302
Concept ID:
C3151952
Finding

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