Fabry Disease 2012

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Summary

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Phenotype

Built up Gb3 and glycosphingolipids may lead to heart attack and stroke

As almost each family has its own private mutation, phenotypes of affected persons can be very variable. In general, with increasing age symptoms become more severe. This effect is due to more and more accumulated glycosphingolipids that cannot be converted by the dysfunctional enzyme. The built up globotriaoslyceramide (Gb3) and related glycosphingolipids in the lysosomes, tissues, blood vessels and organs lead to a malfunction of major organs in the body starting at an age of 30 - 35 (see picture on the right). Thus untreated patients die approximately 10 - 20 years early (females and males, respectively).

Symptoms (onset)

Childhood

  • Acroparesthesia (Numbness in extremities)
  • Hypohidrosis (decreased sweating)
  • Cornea opacity

Acroparesthesia is signaling the clinical onset of Fabry Disease. It is caused by deposited glycosphingolipids in the small blood supplying vessels of the peripheral nerves. Another very typical symptom for Fabry Disease is the whorled streaks and cloudiness of the eye (cornea opacity) resulting from deposits of granular material on the posterior lens capsule.

Adolesence

  • Gastro Intestinal Manifestation - GIM (nausea, vomitting)
  • Angiokeratoma
  • Depression
  • Heat/cold intolerance
  • Fatigue

The GIM results from accumulated Gb-3 in small intestinal vessels and autonomic ganglia of the intestinal. Eventually this often leads to a weight loss of the patient. From early stages on psychosocial manifestations like depression and fatigue lead to a degression of life quality. In a study [Whybra et al 2004] the occurence of angiokeratomas correlated with the severity of Fabry disease and its systemic manifestation.

Adulthood

  • Renal Disease
    • Proteinuria (excess of serum proteins in the urine)
    • Progressive renal insufficiency
    • End-stage renal disease
  • Cardiac Disease
    • Hypertension (high blood pressure)
    • Cardiomyopathy
  • Central Nervous System Disease
    • Headache
    • Stroke
    • Ischaemic cerebrovascular events
    • Binswanger’s Disease (Vascular dementia)

According to FOS, the most common cause of death were renal failure (males) and cerebrovascular disease (females), whereas Waldek et al claim that the principal cause of death is cardiovascular disease. Most of these diseased patients had received a kidney transplant. Again, all these symptoms are in consequence of progressive glycosphingolipid deposition mostly in vessels and in the lysosomes.

Atypical variants

It is believed that late onset variants mostly with specific mutations are underdiagnosed, because of the missing typical early onset symptoms like acroparesthesia and cornea opacity. According to Rolfs et el. patients with these variants in the majority of cases have missense or splicing mutations leading to a residual α-galactosidase A enzyme activity.

Cardiac variant

This variant does not affect patients until their sixth to eighth decade. Usually a hypertrophic cardiomyopathy is diagnosed. Besides from a mild to moderate proteinuria, due to accumulated Gb-3 in the podocytes, no involvement of the kidney is observed.

Renal variant

Many patients with this variant are misdiagnosed, because about 80% of them do not show any signs of angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. However they had moderate to severe left ventricular hypertrophy.

Major manifestations in Classic and atypical Fabry Disease

see source

Manifestation Classic Renal variant Cardiac variant
Age at onset 4-8 years > 25 years > 40 years
Average age of death 41 years > 60 years > 60 years
Angiokeratoma ++ - -
Acroparesthesia ++ -/+ -
Hypohidrosis ++ -/+ -
Corneal opacity ++ - -
Heart Left ventricular hypertrophy, Ischemia Left ventricular hypertrophy Left ventricular hypertrophy, myopathy
Brain Transient ischemic attack - -
Kidney End stage renal disease End stage renal disease Proteinuria
Residual α-Gal A activity < 1% > 1% > 1%

+ = Present, - = Absent

Cross-references

Diagnosis

As described in Symptoms, the diversity of symptoms and especially the lack of early onset ones in the atypical variants make Fabry desease hard to diagnose. Thus it is believed that the number of patients suffering from Fabry Disease is underestimated.

Presumptive Diagnosis

Most cases of Fabry Disease are revealed due to a family member being diagnosed. Also, in a lot of cases observation of early onset symptoms like angiokeratoma and acroparesthesia lead to further testing and eventually to the diagnosis Fabry Disease. Other symptoms that are associated with the disease may also be initiation of further examination.

  • Observation of symptoms
  • Family history
  • Lab findings
    • Kidney biopsy (Renal disease)
    • Oculist findings (Cornea Opacity)
    • MRI (Cardiac disease)
    • Echocardiography (Cardiac disease)

Definitive Diagnosis

After a presumptive diagnosis, there is a demand in substantiating this suspicion. The first step would be an enzyme assay. Usually a fluorometric assay is performed, where the difference in the fluorescence of substrate (4-methylumbelliferyl-α-D-galactopyranoside) and product is measured. Thereby, the enzymatic activity of α-Gal A may be measured. Less than 1% of normal enzyme activity is an indication of classic Fabry Disease, more than 1%, but still decreased activity, indicates atypical variants (see section Major manifestations in Classic and atypical Fabry Disease). This method is not sufficient for female carrier detection. Due to random X Chromosome inactivation some females have a normal or only little decreased enzyme activity.

Thus molecular genetic testing is necessary. This method is also useful for early detection and thus treatment at an early stage if family history is known. Most of the times full gene sequencing is needed, where the mutation in the GLA gene is detected. Almost 100 % of affected males, but less than 100% of affected females can be detected. Mutations in heterozygous females may not be detected, as well as deletion or duplications in the gene of both sexes (PCR fails in this case). Thus targeted mutation analysis can be performed, if the private mutation of the respective family is known. Otherwise, if a partial or whole gene deletion is suspected, several methods, including quantitativ PCR and multiplex ligation-dependant probe amplification, can be applied.

  • Enzyme Assay (Plasma, leukocytes, tissue, urine)
  • Gene Mutation Analysis
    • Sequence analysis
    • Targeted mutation analysis
    • Deletion testing

All listed diagnosis methods may be performed prenatal.

Cross-references

Treatment

Symptom management

Usually, Fabry Disease is diagnosed after the onset of symptoms. Thus, manifestations need to be treated individually.

  • Acroparesthesia: The pain in the extremities is reduced by administering agents that interfere with the sodium channel, such as Diphenylhydantoin.
  • Renal Disease:\tas

Prevention of early symptoms

Prevention of late onset symptoms

Cross-references

Biochemical disease mechanism

Fabry-glycosphingolipid biosynthesis globoseries.png


Cross-references

Mutations

Mutation counts according to HGMD
Mutation type # of public mutations # of commerical mutations
Missense/nonsense 354 441
Small deletions 74 97
Small insertions 29 32
Splicing 28 34
Gross deletions 16 27
Small indels 8 10
Complex rearrangements 3 6
Gross insertions/duplications 1 4
Regulatory 1 2
Repeat variations 0 0
Total 514 653


Reference sequence

Reference Sequence of α-galactosidase A from Uniprot entry P06280 

>gi|4504009|ref|NP_000160.1| alpha-galactosidase A precursor [Homo sapiens]
MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEPDSCISEKLFM
EMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQLANYVHSKGLKLGIYADVGNK
TCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENLADGYKHMSLALNRTGRSIVYSCEWPLYMWP
FQKPNYTEIRQYCNHWRNFADIDDSWKSIKSILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQ
VTQMALWAIMAAPLFMSNDLRHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWA
VAMINRQEIGGPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT
MQMSLKDLL
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