Anderson-Fabry Disease: A Rare Disease That Mimics Common Cardiac, Neurological, Renal, and Other Disorders: Approach for the Differential Diagnosis and Follow-Up

Beirão, Idalina; Cabrita, Ana; Torres, Márcia; Silva, Fernando; Aguiar, Patricio; Gomes, Ana Marta

doi:10.1177/2326409816669372

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Journal of Inborn Errors of Metabolism and Screening

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Review Article • J. inborn errors metab. screen. 4 • 2016 • https://doi.org/10.1177/2326409816669372 copy

Anderson-Fabry Disease: A Rare Disease That Mimics Common Cardiac, Neurological, Renal, and Other Disorders: Approach for the Differential Diagnosis and Follow-Up

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Anderson-Fabry disease (AFD) is a rare inherited X-linked disease, caused by mutations of the gene encoding the α-galactosidase A enzyme, that leads to a deficiency or absence of its activity with consequent accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in the lysosomes of several cells types in the organism, mainly the endothelial, nervous system, cardiac, and renal cells. Its heterogeneous and nonspecific presentation, similar to other common pathologies, delays the diagnosis and leads to incorrect therapy. In the presence of attenuated phenotypes with predominant involvement of an organ, it is even harder to identify patients with AFD. It is highly important to be aware of this diagnosis, since enzyme replacement therapy is currently available. This review aims to approach the clinical manifestations of AFD and the phenotypes related to the differential diagnosis for each manifestation and the frequency of follow-up recommended.

Keywords
Anderson-Fabry disease; alpha-galactosidase A; proteinuria; leucoencephalopathy; angiokeratoma; chronic diarrhea; persistent abdominal pain; acroparesthesia; hypohidrosis

Symptom		Most Common Differential Diagnosis		Fabry Symptoms for Differentiation
Arthralgia, increased		Rheumatoid arthritis (joint pain, Raynaud’s phenomenon,		Fabry symptoms: paresthesias, intolerance to heat/cold,
	sedimentation		and positive rheumatoid factor)		hypo- or hyperhidrosis, angiokeratomas, abdominal
	rate				pain, or diarrhea; cornea verticillata; compatible family
					history. The absence of synovial inflammation
		Rheumatic fever (migratory polyarthritis involving		Nonmigratory arthralgias in the hands and feet; Fabry
			ankles, wrists, knees, and elbows with edema, usually		symptoms; cornea verticillata; compatible family history
			spares hands and feet). Usually self-limited (lasting less
			than 1 month)
		Juvenile dermatomyositis (rare autoimmune disease;
			heliotropic dermatitis; and elevated muscle enzymes)
		Juvenile idiopathic arthritis—chronic arthritis of
			unknown cause that occurs in children and
			adolescents under 16 years
Pain in the limbs		Growth crises (recurrent, self-limited in the lower		Neuropathic pain induced by fever, temperature changes
			extremities at the end of the day and night)		or exercise, hypohidrosis. Mean age of onset: 1^a decade
					in boys and a decade later in girls
Acute pain with no		Psychiatric illness (no other manifestations of AFD)		Proteinuria, left ventricular hypertrophy, angiokeratomas,
	apparent cause				and cornea verticillata
		Fibromyalgia (the absence of other manifestations of AFD)
Peripheral pain and		Raynaud’s phenomenon (color changes in the fingers		More common in men with classic phenotype. Other
	temperature		triggered by cold, 80% are women. It is associated with		symptoms of AFD
	sensitivity		autoimmune diseases)
Transient ischemic		Multiple sclerosis (can be accompanied by pain in the		The presence of angiokeratomas, cornea verticillata,
	attacks		extremities and abdominal pain)		proteinuria, and left ventricular hypertrophy
		Migraine with aura
		Conversive crisis
Angiokeratomas		Hereditary hemorrhagic telangiectasia (autosomal-		X-linked transmission; predominance in the hips,
			dominant transmission; telangiectasia in the skin,		buttocks, and genital area. No bleeding diathesis
			mucous membranes, and internal organs; recurrent
			epistaxis in adolescence; gastrointestinal bleeding)
		Ataxia telangiectasia (autosomal-recessive transmission;		Lesions located predominantly in the hips,
			skin and conjunctival telangiectasias in areas exposed to		buttocks, and genital area. No ataxia
			light; neurological symptoms predominate)
Abdominal pain		Inflammatory bowel disease		Fabry symptoms, proteinuria, cornea verticillata, and
					angiokeratomas
		AppendicitisMesenteric lymphadenitis		Abdominal pain associated with acroparesthesia
Recurrent		Irritable bowel syndrome		Abdominal pain associated with neuropathic pain,
	abdominal pain				angiokeratomas, proteinuria
	and altered bowel
	habits
Tinnitus and vertigo		Meniere disease		Fabry symptoms, cornea verticillata, angiokeratomas

		Disease		Clinical Features		Diagnosis
Common Causes		Arterial		5% to 10% secondary causes		ECG: LVH; ECHO: LVH concentric
			hypertension	Fundoscopic changes		Genetics: useless
				Lost nocturnal dip		Other: identification of secondary causes
		Aortic stenosis		Slow-rising pulse		ECG: LVH; ECHO: LV/AO gradient, valve area
				Ejection systolic murmur		Cardiac MRI: morphology and valve area
				↓ S2		Genetics: useless
						Laboratory: nonspecific
		Obesity		Body mass index		ECG: LVH (≈ 10%); ECHO: LVH concentric epicardial fat
				Waist circumference		Cardiac MRI: useful if poor acoustic window
				LVH regression with weight loss		Genetics: monogenic defects, eg, leptin deficit
						Other: endocrine causes
Physiologic LVH		Athletic heart		High level of endurance training		ECG: LVH; ECHO: mild LVH (= 13 mm), LV dilatation,
				Resting bradycardia			without diastolic dysfunction or longitudinal
				LVH regression with deconditioning			dysfunction
						Cardiac MRI: no late gadolinium enhancement
						Genetics: useless
						Other: VO₂max = predicted
Sarcomeric protein		Hypertrophic		Family history (population prevalence		ECG: LVH, T-wave inversion in the anterior wall (apical
	disease		cardiomyopathy		1: 500)		variant)
				1st cause of sudden death in young		ECHO: asymmetric LVH (+ common), systolic anterior
					athletes		motion of mitral valve, dynamic LV outflow tract
				Risk stratification for sudden cardiac			obstruction
					death	Cardiac MRI: intramyocardial delayed enhancement
							diffuse
						Genetics: autosomal dominant
						Histology: myofibrillar disarray, fibrosis, small vessel
							disease
Myocardial infiltration		Amyloidosis		Senile amyloidosis frequent (≈20%		ECG: low voltage QRS complex, AV block, AF; ECHO:
					with >80 years). Multisystem		LVH, atrial dilation, LV systolic function preserved, LV
					involvement: proteinuria,		granular appearance, restrictive physiology
					petechiae, hepatosplenomegaly,	Cardiac MRI: global subendocardial late gadolinium
					autonomic and peripheral		enhancement
					neuropathy, macroglossia	Genetics: in familial amyloidosis autosomal dominant
				AL amyloidosis—increased cardiac			(transthyretin)
					involvement	Biopsy: Congo red positive
		Hemochromatosis		Late presentation in females		ECG: LVH; ECHO: LVH, cavities dilation, restrictive
					Transfusion overload		pattern
				Clinical picture includes bronze skin,		Cardiac MRI: rapid signal decay (<20 milliseconds) on T2,
					arthritis, diabetes, and liver		can guide the need for phlebotomy or chelation
					cirrhosis		therapy
						Genetics: HFE gene (autosomal recessive)
						Other: iron kinetic
Unclassified		Left ventricular		Familial in up to 25% of cases		ECG: LVH, supraventricular arrhythmias
	cardiomyopathies		noncompaction	Also observed in other		ECHO: NC/C ratio >2:1. Doppler color: deep perfused
					cardiomyopathies		intertrabecular sinuses
				Typical presentation with triad of		Cardiac MRI: tendency to overdiagnosis
					palpitations, thromboembolism,	Genetics: autosomal dominant (familial cases)
					and/or heart failure
Metabolic diseases		Fabry disease		Lysosomal storage disease		ECG: LVH, short PR (early stages), heart block (late
				α-galactosidase deficiency			stages)
				Multisystemic disease		ECHO: concentric LVH, right ventricular, and papillary
				Enzyme replacement therapy			muscles hypertrophy are common
					available	Cardiac MRI: late enhancement in inferoposterior wall
							(spares subendocardium)
						Genetics: X-linked transmission
						Lab: proteinuria and increased serum creatinine
		Pompe disease		Glycogen storage disease (type II)		ECG: LVH, short PR (early stages), accessory pathways
				Acid maltase deficiency			(rare in late onset forms)
				Early onset: survival beyond 1 year		ECHO: concentric LVH, restrictive physiology (rare in
					unusual		late onset forms)
				Late onset: after 1 year of age can		Cardiac MRI: nonspecific
					occur in adulthood (rare cardiac	Genetics: autosomal recessive
					involvement)	Lab: ↑ serum CPK, no fasting hypoglycemia, muscle
					Limb-girdle myopathy and		biopsy
					respiratory muscles weakness
				Enzyme replacement therapy available
		Danon disease		Lysosomal glycogen storage disease:		ECG: LVH, short PR, accessory pathways
				LAMP2 deficiency (lysosomal		ECHO: concentric LVH with restrictive physiology
					membrane transporter protein)	Cardiac MRI: nonspecific
				Males present in childhood, females		Genetics: X-linked dominant
					in early adulthood	Lab: ↓ LAMP2 activity
				Myopathy and mental retardation		muscle biopsy
		PRKAG2		Lysosomal glycogen storage disease		ECG: LVH, short PR, accessory pathways
				AMP-activated protein kinase γ2		ECHO: concentric LVH with restrictive physiology
					gene mutation	Cardiac MRI: nonspecific
				Multisystem involvement rare		Genetics: autosomal dominant
		Primary carnitine		Fatty acid oxidation disorder		ECG: LVH
			deficiency	Functional carnitine transporter		ECHO: concentric LVH with restrictive physiology
					deficiency	Cardiac MRI: nonspecific
				Most frequent presentation in infancy		Genetics: autosomal recessive
				Myopathy, hepatomegaly, abnormal		Lab: hypoglycemia, hyperammonemia
					fatty acid metabolism
Mitochondrial		Kayers Sayer		Myopathy and mitochondrial disease		ECG: LVH
	myopathies	MERRF syndrome		Heart: LVH and arrhythmias		ECHO: concentric LVH with restrictive physiology
Multiple varieties		MELAS syndrome		Neurological: ataxia, stroke,		Cardiac MRI: nonspecific
(examples)					ophthalmoplegia, ptosis,	Genetics: mitochondrial DNA mutations
					nystagmus, retinitis pigmentosa	Muscle biopsy: typical ragged red fibers
Syndromic		Noonan		Common: 1:1000 live births		ECG: LVH
	conditions			Facial dysmorphia		ECHO: LVH, pulmonary stenosis, septal defects
Multiple varieties				Short stature		Cardiac MRI: nonspecific
(examples)						Genetics: autosomal dominant or sporadic (mutations
							involving growth hormone proteins)
		Friedreich ataxia		Rare: 1: 135 000 live births		ECG: LVH
				Ataxia, dysarthria, diabetes, motor		ECHO: LVH
					neuropathy	Cardiac MRI: nonspecific
						Genetics: autosomal recessive (involving proteins
							associated with mitochondrial iron metabolism)

Symptom		Most Common Differential Diagnosis	Features for Differentiation
Albuminuria/		IgA nephropathy	Microscopic hematuria (rare in AFD)
	proteinuria		Recurrent macroscopic hematuria (very rare in AFD)
	microhematuria		Pathologically, mesangial proliferation with prominent IgA deposition is observed in almost all
Hypertension				biopsies
Decrease of GFR		Focal and segmental	Nephrotic syndrome is a common clinical presenting feature (>70% of patients)
		glomerulosclerosis	Severe hypertension can be present
			Histopathological findings: segmental sclerosis of the glomerular tuft with obliteration of
				glomerular capillaries by accumulation of acellular matrix and hyaline deposits, along with
				adhesion to the Bowman capsule
			Fusion of diffuse foot process, predominantly in the sclerotic segments, that can be also observed
				in AFD
		Alport syndrome	Hematuria is the most common and earliest manifestation of Alport syndrome (rare in AFD)
			Sensorineural deafness
			Ocular manifestations: anterior lenticonus; dot-and-fleck retinopathy; posterior polymorphous
				corneal dystrophy and temporal macular thinning
			Renal biopsy: ultrastructural abnormalities—splitting and lamellation of the glomerular basement
				membrane

Organ System	Assessment		Recommendation
General	SF-36 Health Survey		Every 12 months
	Genetic counselling		Baseline; if new data
	Genotype		If not previously determined
	Vascular risk factors assessment: cholesterol (total, LDL,		Every 12 months
		HDL), triglycerides
	Lipoprotein a, total plasma homocysteine, factor V Leiden,		Baseline
		protein C, protein S, prothrombin G20210A mutation,
		antithrombin III, antiphospholipid antibodies
Renal	Creatinine, urea, serum electrolytes, renal ultrasound		Baseline
	24-hour Urine: proteins, creatinine, sodium or		Every 12 months: CKD stage 1 to 2 and proteinuria <1 g/d
	Spot urine: protein/creatinine ratio, albumin/creatinine ratio		Every 6 months: CKD stage 3 and proteinuria <1 g/d Every 3 months: proteinuria >1 g/d or CKD stage 4
Cardiac	Palpitations, angina		Baseline Every 6 months
	Blood pressure, rhythm		Every evaluation visit
	ECG, echocardiography		Baseline Every 12 months
	Holter		Baseline Every 12 months
	Event monitoring		If an arrhythmia is suspected or palpitations are present
	Cardiac MRI		Baseline Revaluation accordingto clinical and echocardiographicfindings
	Coronary angiography		If clinical signs of ischemia
Neurologic	Paresthesias, painful crises, intolerance to cold and heat,		Baseline
		focal symptoms	Every 6 months
	Neurologic examination, brief pain, neuropathic pain in		Baseline
		4 questions	Every 6 months
	Brain MRI		Baseline, if TIA or stroke event; biannually or annually if
				white matter lesions
	Study of cervical and intracranial vessels (angio MRI and/or		If cerebrovascular event
		ultrasound)
	Neurophysiological tests for small-fiber neuropathy		At baseline
ENT	Tinnitus, hearing loss, vertigo		Baseline
			Every 6 months
	Audiometry		Baseline
			Every 24 months
Ophthalmologic	General eye examination		Baseline
			Every 12 months
Pulmonology	Cough, exercise dyspnea, wheezing, exercise intolerance		Baseline
			Every 6 months
	Spirometry (including response to bronchodilators),		Baseline
		cardiopulmonary exercise testing, oximetry, chest X-ray	Every 24 months or if clinical indications
Gastrointestinal	Postprandial abdominal pain, bloating, early satiety, diarrhea,		Baseline
		nausea, vomiting, failure to thrive	Every 6 months
	Endoscopic or radiological evaluation		If symptoms persist or worsen despite treatment

Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br

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[1] Corresponding Author: Idalina Beirão, Centro Hospitalar do Porto, Largo Professor Abel Salazar, 2, Porto 4099-001, Portugal. Email: idalina.m.b@gmail.com

Differential Diagnosis
Diabetes mellitus
Vitamin B12 deficiency and vitamin B6 toxicity
Amyloidosis (hereditary or acquired)
Acute intermittent porphyria
Vasculitis
Connective tissue diseases, sarcoidosis
Immuno-mediated: postinfectious, associated with other autoimmune
	diseases
Neurotoxic drugs: retroviral, cytostatics, metronidazole, and
	linezulide
Infections: HIV, HCV, Lyme disease, Hansen disease
Toxic: alcohol, heavy metals
Sensitive and autonomic hereditary neuropathies