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Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome(GD3C)

MedGen UID:
341563
Concept ID:
C1856476
Disease or Syndrome
Synonyms: Gaucher disease type 3C; Gaucher Disease, Cardiovascular Form; GAUCHER DISEASE, TYPE IIIC
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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).
 
Gene (location): GBA1 (1q22)
 
Monarch Initiative: MONDO:0009268
OMIM®: 231005
Orphanet: ORPHA2072

Disease characteristics

Excerpted from the GeneReview: Gaucher Disease
Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal-lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity. Type 1 GD is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and the absence of primary central nervous system disease. Type 2 GD is characterized by primary central nervous system disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years. Type 3 GD is characterized by primary central nervous system disease with childhood onset, a more slowly progressive course, and survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. [from GeneReviews]
Authors:
Derralynn A Hughes  |  Gregory M Pastores   view full author information

Additional descriptions

From OMIM
Gaucher disease type IIIc (GD3C) is a rare variant of subacute neuronopathic Gaucher disease type III (231000), but is considered distinct because of its association with cardiovascular calcifications (Bohlega et al., 2000).  http://www.omim.org/entry/231005
From MedlinePlus Genetics
The most severe type of Gaucher disease is a very rare form of type 2 called the perinatal lethal form. This condition causes severe or life-threatening complications starting before birth or in infancy. Features of the perinatal lethal form can include extensive swelling caused by fluid accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or other skin abnormalities; hepatosplenomegaly; distinctive facial features; and serious neurological problems. As its name indicates, most infants with the perinatal lethal form of Gaucher disease survive for only a few days after birth.

Types 2 and 3 Gaucher disease are known as neuronopathic forms of the disorder because they are characterized by problems that affect the central nervous system. In addition to the signs and symptoms described above, these conditions can cause abnormal eye movements, seizures, and brain damage. Type 2 Gaucher disease usually causes life-threatening medical problems beginning in infancy. Type 3 Gaucher disease also affects the nervous system, but it tends to worsen more slowly than type 2.

Type 1 Gaucher disease is the most common form of this condition. Type 1 is also called non-neuronopathic Gaucher disease because the brain and spinal cord (the central nervous system) are usually not affected. The features of this condition range from mild to severe and may appear anytime from childhood to adulthood. Major signs and symptoms include enlargement of the liver and spleen (hepatosplenomegaly), a low number of red blood cells (anemia), easy bruising caused by a decrease in blood platelets (thrombocytopenia), bone abnormalities such as bone pain and fractures, and joint conditions such as arthritis.

Another form of Gaucher disease is known as the cardiovascular type (or type 3c) because it primarily affects the heart, causing the heart valves to harden (calcify). People with the cardiovascular form of Gaucher disease may also have eye abnormalities, bone disease, and mild enlargement of the spleen (splenomegaly).

Gaucher disease is an inherited disorder that affects many of the body's organs and tissues. The signs and symptoms of this condition vary widely among affected individuals. Researchers have described several types of Gaucher disease based on their characteristic features.  https://medlineplus.gov/genetics/condition/gaucher-disease

Clinical features

From HPO
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Mitral stenosis
MedGen UID:
44466
Concept ID:
C0026269
Disease or Syndrome
An abnormal narrowing of the orifice of the mitral valve.
Aortic valve calcification
MedGen UID:
140899
Concept ID:
C0428791
Disease or Syndrome
Deposition of calcium salts in the aortic valve.
Mitral valve calcification
MedGen UID:
181575
Concept ID:
C0919718
Disease or Syndrome
Abnormal calcification of the mitral valve.
Calcification of the aorta
MedGen UID:
202111
Concept ID:
C1096249
Pathologic Function
Calcification, that is, pathological deposition of calcium salts in the aorta.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
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.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Supranuclear ophthalmoplegia
MedGen UID:
235616
Concept ID:
C1408507
Disease or Syndrome
A vertical gaze palsy with inability to direct the gaze of the eyes downwards.
Slowed horizontal saccades
MedGen UID:
341564
Concept ID:
C1856477
Finding
An abnormally slow velocity of horizontal saccadic eye movements.
Hypometric horizontal saccades
MedGen UID:
341565
Concept ID:
C1856478
Finding
Saccadic undershoot of horizontal saccadic eye movements, i.e., a horizontal saccadic eye movement that has less than the magnitude that would be required to gain fixation of the object.

Professional guidelines

PubMed

Nitschke Y, Rutsch F
Curr Osteoporos Rep 2017 Aug;15(4):255-270. doi: 10.1007/s11914-017-0370-3. PMID: 28585220

Recent clinical studies

Etiology

Rutsch F, Buers I, Nitschke Y
Arterioscler Thromb Vasc Biol 2021 Jan;41(1):35-47. Epub 2020 Nov 12 doi: 10.1161/ATVBAHA.120.315577. PMID: 33176451
Nitschke Y, Rutsch F
Curr Osteoporos Rep 2017 Aug;15(4):255-270. doi: 10.1007/s11914-017-0370-3. PMID: 28585220
Kumar KR, Lohmann K, Klein C
Curr Opin Neurol 2012 Aug;25(4):466-74. doi: 10.1097/WCO.0b013e3283547627. PMID: 22772876
Kessler M, Netter P, Azoulay E, Mayeux D, Pere P, Gaucher A
Br J Rheumatol 1992 Mar;31(3):157-62. doi: 10.1093/rheumatology/31.3.157. PMID: 1540782

Diagnosis

Loret A, Jacob C, Mammou S, Bigot A, Blasco H, Audemard-Verger A, Schwartz IV, Mulleman D, Maillot F
Orphanet J Rare Dis 2023 Aug 10;18(1):239. doi: 10.1186/s13023-023-02810-6. PMID: 37563694Free PMC Article
Rutsch F, Buers I, Nitschke Y
Arterioscler Thromb Vasc Biol 2021 Jan;41(1):35-47. Epub 2020 Nov 12 doi: 10.1161/ATVBAHA.120.315577. PMID: 33176451
Krishna SH, McKinney AM, Lucato LT
Semin Ultrasound CT MR 2014 Apr;35(2):160-91. Epub 2013 Oct 23 doi: 10.1053/j.sult.2013.10.008. PMID: 24745891
Kessler M, Netter P, Azoulay E, Mayeux D, Pere P, Gaucher A
Br J Rheumatol 1992 Mar;31(3):157-62. doi: 10.1093/rheumatology/31.3.157. PMID: 1540782

Therapy

Allgrove J
J Pediatr Endocrinol Metab 2002;15 Suppl 3:921-8. PMID: 12199351
Kessler M, Netter P, Azoulay E, Mayeux D, Pere P, Gaucher A
Br J Rheumatol 1992 Mar;31(3):157-62. doi: 10.1093/rheumatology/31.3.157. PMID: 1540782

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