What is Gaucher disease Type 3?

Gaucher disease Type 3 is a chronic neuronopathic form of the disease that manifests in childhood and progresses slowly throughout the lifespan.1 The visceral manifestations of Gaucher disease Type 3 are similar to those of Gaucher disease Type 1 but are often combined with oculomotor involvement, which in most cases occurs before patients reach the age of 20 years.2

Gaucher disease Type 3 can be further classified into three subtypes1:

  • Gaucher disease Type 3a: dominant neurological manifestations and mild visceral disease
  • Gaucher disease Type 3b: dominant visceral disease and skeletal manifestations with mild neurological signs
  • Gaucher disease Type 3c: visceral disease associated with cardiac involvement (also known as cardiovascular Gaucher disease).

In addition to the classification of Gaucher disease Type 3 into subtypes, it has been proposed that since Gaucher disease Type 3 may present between infancy, adolescence and adulthood, there is a continuum of different clinical presentations.1,3 Moreover, the neurological manifestations of patients with neuronopathic Gaucher disease (Types 2 or 3) are also proposed to represent a continuum of symptoms, ranging from the most severe perinatal cases to mild neurological involvement.4

Neurological involvement

The clinical presentation of Gaucher disease Type 3 is heterogeneous, especially in terms of neurological involvement.2 Some patients may present with moderate systemic involvement, and horizontal ophthalmoplegia (paralysis or weakness of one or more muscles that control horizontal eye movement)5 may be the first neurological presenting symptom.6 Other typical neurological manifestations may include cerebellar ataxia, developmental delay, extrapyramidal features, myoclonic or generalised seizures, and supranuclear ophthalmoplegia.6

Clinical features may include supranuclear saccadic gaze palsy, which is the most consistent clinical feature of Gaucher disease Type 3.7,8 Saccade is defined as ‘quick eye movement’, and in Gaucher disease Type 3, saccade may slow or fail to initiate.9 During infancy, saccade can be difficult to detect, but is observed in children when they turn around while walking, or by horizontal head jerks during reading as they attempt to compensate for the saccadic deficit; vertical movements are often affected too. Patients with Gaucher disease Type 3 may learn to counteract their poor saccades (via synkinetic blinking, looping and head thrusting) but these movements can cause functional disability while driving, crossing the street or reading.7 Patients with Gaucher disease Type 3 may also exhibit the following: abnormal brainstem evoked potentials; seizures, including myoclonic seizures; or motor characteristics such as tremors.6,10

Visceral disease

Patients with Gaucher disease Type 3 may have severe visceral disease and may also demonstrate pulmonary involvement, including shortness of breath during exercise, and coughing and wheezing, which may lead to vomiting.2,6,11

Clinical features of Gaucher disease Type 3: International Collaborative Gaucher Group (ICGG) Neurological Outcomes Subregistry 2010

As of 1 June 2007, 4760 patients were enrolled in the ICGG Gaucher Registry (sponsored by Sanofi Genzyme), 131 of whom were enrolled in the Neurological Outcomes Subregistry. The mean (standard deviation [SD]) age at diagnosis of Gaucher disease Type 3 was 3.2 (6.2) years, with approximately equal numbers of males (47%) and females (53%) included in the study. Patients were from Egypt (31%), the UK (14%), Poland (13%), Sweden (11%), the US (10%) or other countries (21%).6

Neurological manifestations were first observed before the age of 2 years in 47% of patients (61/131), and were observed in 41% when they were aged ≥2 years (54/131; data unknown for 16 patients). Of the 125 patients who could provide these data, developmental delay, as assessed by the treating physician, was reported in 54 (43%) patients.6

 

The prevalence of cranial nerve characteristics was reported as follows6:

  • 71% abnormal horizontal gaze (n=87/123)
  • 63% head movement rather than eye movement problems (n=76/121)
  • 55% head thrusting (n=66/119)
  • 45% abnormal vertical gaze (n=55/123)
  • 43% abnormal slow tracking (n=53/123)
  • 36% convergent squint (n=44/121)
  • 22% dysarthria* (n=26/120)
  • 20% swallowing difficulties (n=24/123)
  • 11% chewing difficulties (n=14/122)
  • 11% stridor (n=13/120)
  • 7% retroflexion of the head (n=8/122).

The most frequent motor alterations included6:

  • 25% muscle weakness (n=30/120)
  • 18% extrapyramidal features (n=21/116)
  • 15% spasticity (n=18/122)
  • 24% intention tremor (n=29/121)
  • 16% tremor at rest (n=19/121)
  • 16% seizures (n=19/122; 6% tonic-clonic; 4% clonic; 3% tonic; 2% myoclonic; 2% typical absence; 1% atypical absence).

The most common haematological and visceral disease manifestations were6:

  • 100% moderate or severe splenomegaly (n=35/35)
  • 97% moderate or severe hepatomegaly (n=30/31)
  • 60% anaemia (n=39/65)
  • 56% paediatric growth delay (n=36/64)
  • 52% moderate or severe thrombocytopaenia in non-splenectomised patients (n=33/63)
  • 11% bone pain (n=6/53)
  • 2% bone crises (n=1/53).

TYPE 3 SUBTYPES

Gaucher disease Type 3a is characterised by mild-to-severe systemic disease, neurological manifestations and myoclonic seizures. The clinical picture of a patient with Gaucher disease Type 3a may be identical to progressive myoclonic epilepsy, with or without horizontal supranuclear gaze palsy, and mild systemic findings.12

The symptoms of Gaucher disease Type 3b are relatively mild neurological symptoms such as isolated supranuclear gaze palsy (often manifesting as ocular motor apraxia) with severe visceral involvement, similar to patients with Gaucher disease Type 1.13 Bone involvement in patients with Gaucher disease Type 3b is comparable with that in patients with Gaucher disease Type 1. However, pulmonary infiltrates, thoracic lymph-node enlargement, vertebral compression fractures and avascular necrosis of the long bones may occur more frequently in patients with Gaucher disease Type 3b.14

Gaucher disease Type 3c, also known as cardiovascular Gaucher disease, manifests primarily as aortic and cardiac valve calcifications.15,16 Patients with Gaucher disease Type 3c are homozygous for the GBA1 mutation D409H (c.1342G>C; p.Asp448His; see genetic inheritance of Gaucher disease).17

Clinical features of Gaucher disease Type 3c: a review of the literature

A study published in 2019 reviewed the literature and identified 36 patients with Gaucher disease Type 3c. These patients presented primarily with cardiovascular calcifications. Four additional patients with Gaucher disease Type 3c with rare cardiovascular, pulmonary and psychiatric findings and atypical disease courses, were also described.17

Among the patients with confirmed homozygosity (n=28) for the D409H (c.1342G>C; p.Asp448His) mutation included in this study, the youngest age at diagnosis was 1.5 months (a Spanish patient), whereas one Japanese patient was diagnosed with the disease at age 42 years. The geographic locations of these patients were as follows: 5 were Spanish, 5 were of Israeli citizenship, 4 were Turkish, 3 were Palestinian, 3 were Japanese, 3 were Saudi Arabian, 1 was American, 1 was British/German, 1 was Greek, 1 was Indian and 1 was Mexican.17

The following clinical characteristics were identified in the 40 patients with Gaucher disease Type 3c17:

  • 77.5% valve calcification and stenosis or regurgitation
  • 77.5% aortic and mitral valve involvement
  • 45.5% calcification of the aorta
  • 15.0% other artery involvement
  • 15.0% aorta or valve, fibrosis, atherosclerosis or uncalcified stenosis
  • 7.5% arrhythmia or abnormal electrocardiogram
  • 5.0% other valves involvement
  • 5.0% other or poorly described
  • 2.5% arterial thrombosis.
  • 72.5% oculomotor apraxia or abnormal eye movements
  • 62.5% corneal opacities.
  • 45.0% hydrocephalus or ventriculomegaly§
  • 32.5% other abnormal brain imaging
  • 17.5% impaired intelligence
  • 12.5% hyperflexia
  • 10.0% seizures or convulsions
  • 10.0% spastic paraplegia or ataxia
  • 10.0% hearing loss
  • 5.0% hypoflexia
  • 5.0% leptomeningeal fibrosis||
  • 2.5% psychiatric disorder.
  • 47.5% splenomegaly
  • 30.0% hepatomegaly.
  • 30.0% pancytopaenia#
  • 7.5% thrombocytopaenia
  • 5.0% anaemia.
  • 17.5% skeletal defects
  • 17.5% other
  • 12.5% poor growth
  • 5.0% lung fibrosis or interstitial disease
  • 5.0% connective tissue disease.


These data suggest that Gaucher disease Type 3c is mainly characterised by calcifications of the ascending aorta and the aortic and mitral valves. Also evident were the neurological findings of oculomotor apraxia, as well as more disease-related features, such as pancytopaenia and organomegaly, which were usually observed as mild.17

In patients with Gaucher disease Type 3c, the main morbidity is heart failure due to cardiac valve calcification, causing stenosis which, if left untreated, can lead to death during the second decade of life.17

What is the Norrbottnian clinical variant of Gaucher disease?

The Norrbottnian clinical variant of Gaucher disease is a well-defined nosological entity characterised by early-onset significant hepatosplenomegaly, which typically requires splenectomy at an early age.18,19 During the first or second year of life, neurological involvement generally occurs, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment.18 In the spine, osteopaenia may occur, causing severe and progressive excessive curvature of the upper spine.18 This form of Gaucher disease is unique to the neuronopathic variant (L444P [c.1448T>C; p.Leu483Pro]; see genetic inheritance of Gaucher disease) of Gaucher disease Type 3, and is thought to have originated in the province of Norrbotten in Sweden.20 Disease phenotypes similar to the Norbottnian clinical variant of Gaucher disease have also been reported in Poland and Southern Italy.18,21

 

*Speech difficulties
22Noisy breathing, usually caused by an infection that covers the opening of the trachea in children23
Abnormal extension of ventricles within the brain causing the accumulation of cerebrospinal fluid5
§Gross enlargement of a ventricle of the brain24
||A fibrosis reaction within the subarachnoid space, which could be a result of infectious or chemical meningitis25
#An abnormally low level of red and white blood cells, as well as platelets, in the circulating blood26

C-ANPROM/INT//7566; Date of preparation: September 2020