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doi:10.1111/jpc.12732

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Diagnostic dilemma and delay in Fabry disease: Insights from a case series of young female patients Carolyn Ellaway Western Sydney Genetics Program, Children’s Hospital at Westmead, Sydney, New South Wales, Australia

Fabry disease is a rare, progressive, X-linked inborn error of the glycosphingolipid metabolic pathway. It is found among all ethnic, racial and demographic groups. In males, the estimated incidence is 1 in 50 000, and recent population estimates range from 1 in 80 000 to 1 in 117 000, although milder forms of the disease that present later in life may be more common. Fabry disease results from mutations in the GLA gene that encodes the enzyme α-galactosidase A (α-Gal A). Complete or partial deficiency of α-Gal A leads to an accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), within lysosomes of a wide variety of tissues throughout the body. In males, confirmation of a clinical diagnosis requires demonstration of deficient α-Gal A activity or increased Gb3 levels in plasma or urinary sediment. In females, α-Gal A activity and Gb3 levels may be intermediate or normal; diagnosis requires identification of a mutation in the GLA gene or by linkage analysis in cases where a specific gene defect is not established. The symptoms of classical Fabry disease usually present in childhood (mean onset 3–10 years in males and 6–15 years in females).1 The first clinical presentation of Fabry disease is usually episodic neuropathic pain presenting with burning pain in the hands and feet (acroparaesthesia). Recurrent gastrointestinal symptoms and hypohidrosis are also common in the early stage of the disease. Although not life-threatening, these symptoms impact on the health, quality of life and function of affected children. The most serious complications of Fabry disease emerge in adulthood and include end-stage renal failure; cerebrovascular events such as strokes; progressive cardiomyopathy, arrhythmias and valvular disease; and premature death. Despite being X-linked, Fabry disease affects females; symptoms may be more variable, but can be of the same severity as in males.1,2 Our understanding of Fabry disease is increasing, yet misdiagnosis and diagnostic delay frequently occur. Contributing factors include the rarity of the disease and the non-specific, subjective nature of the early symptoms. By way of highlighting

Correspondence: Dr Carolyn Ellaway, Western Sydney Genetics Program, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia. Fax: +61 (0)2 9845 3121; email: carolyn.ellaway@ health.nsw.gov.au Conflict of interest: The author has received reimbursement from Genzyme Australia Pty Ltd for participation in an Australian rare diseases advisory board. Accepted for publication 4 August 2014.

these issues, this paper describes three separate cases of female paediatric patients and presents strategies to aid in reducing diagnostic dilemmas.

Patient Case Histories Initial symptoms Three female patients each presented with a first episode of painful, burning sensation in their feet at an early age (Table 1). Over the following 3–4 years, these patients each experienced recurrent episodes, lasting from several hours to days, at times rendering them unable to walk. Despite numerous consultations with their general practitioners (all three cases) and referrals to a paediatrician (patients 1 and 3), no diagnosis was made. The frequency and severity of painful episodes of feet and hands increased over the following years in all three patients and were exacerbated by extremes of temperature, physical exertion and intercurrent illnesses.

Diagnostic delays Patient 1 was initially diagnosed with possible Raynaud disease variant by her paediatrician and as being flat-footed by a physiotherapist. It was not until she reached 15 years that her family medical history was interrogated. Her father had many medical problems, including cataracts, hypertrophic cardiomyopathy, tinnitus, angiokeratomas and end-stage renal failure and had required kidney transplantation. A renal biopsy showed accumulation of glycosphingolipids; his α-Gal A activity was reduced, and a mutation in the GLA gene was identified. This patient was subsequently referred to a genetic metabolic physician and found to have the same mutation in the GLA gene that had previously been identified in her father. Patient 2 (at age 10 years) was noted to have a corneal abnormality by an optometrist and was prescribed glasses for hypermetropia. Occasional headaches were also reported. When the patient was 12, her optometrist found vortex keratopathy (Fig. 1) during a routine eye examination. After referral to a paediatric ophthalmologist, vortex keratopathy, hypermetropia, conjunctival vessel dilatation and occasional dot aneurysm were also noted. At this time other symptoms, such as recurrent abdominal pain and nausea, began to emerge, and the patient was referred to a genetic metabolic physician. There was no family history of Fabry disease; an apparent de novo mutation in the GLA gene was identified and the diagnosis confirmed. Patient 3 (at age 5 years) began to experience recurrent abdominal pain and was diagnosed with constipation and

Journal of Paediatrics and Child Health 51 (2015) 369–372 © 2014 The Author Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

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Table 1 Key patient characteristics

Initial symptom Age at onset of symptoms Age at diagnosis of Fabry disease Key factor leading to diagnosis of Fabry disease α-Galactosidase gene mutation

Patient 1

Patient 2

Patient 3

Acroparaesthesia 7 years 15 years Family history Familial

Acroparaesthesia 6 years 13 years Vortex keratopathy De novo

Acroparaesthesia 4 years 7 years Family history Familial

Drugs Program (details of these criteria are available from http://www.health.gov.au/lsdp#Agalsidase).

Discussion

Fig. 1 Vortex keratopathy (also called cornea verticillata). Vortex keratopathy is characterised by fine, golden-brown or grey, usually bilateral opacities that branch out from a central whorl across the inferior cornea. It is the most frequently reported ophthalmic abnormality in Fabry disease and is seen in both males and females, making ophthalmological examination a useful tool for early diagnosis of Fabry disease.3

possible irritable bowel syndrome. In retrospect, she had complained of acroparaesthesia from approximately 4 years of age. At age 7, after referral to a paediatrician, her family medical history was interrogated. Her uncle had had a kidney transplant for end-stage renal failure and died aged 45 years. Her paternal grandmother had had hypertrophic cardiomyopathy and proteinuria and died aged 70 years. Her father had angiokeratoma and recurrent atrial fibrillation. He had reduced α-Gal A activity, and a mutation in the α-galactosidase gene was identified. This patient was referred to a genetic metabolic physician, after which a familial mutation in the GLA gene was identified and the diagnosis of Fabry disease established.

Management and care post-diagnosis In all three cases, additional investigations revealed no signs of renal or cardiac involvement. Treatment with low-dose, slowrelease carbamazepine was commenced for patients 1 and 2, which initially led to a reduction in the frequency and severity of acroparaesthesias. Patient 2, however, continued to experience recurrent abdominal pain and acroparaesthesias. She started enzyme replacement therapy at 16 years of age. Fabry disease is progressive; therefore, each of these patients is undergoing lifelong surveillance for complications, regular monitoring, and ongoing assessments of eligibility for enzyme replacement therapy, based on the criteria set by the Life Saving 370

The three female paediatric patient cases described in this paper were first diagnosed with other medical conditions and demonstrate a substantial delay in the time to confirmation of a diagnosis of Fabry disease. Initial misdiagnosis and diagnostic delay are consistent with other reports in the literature.4–6 Contemporary evidence has established that heterozygous females should be regarded as potential patients and not simply as asymptomatic carriers of Fabry disease.7 The disease in females can be as severe as in males, although the symptoms and signs are more variable with a slower rate of progression. Lack of consideration of Fabry disease as a possibility, particularly in young female patients, is one of the major challenges to making a correct and timely diagnosis. Children may first present with non-specific or unusual symptoms, which, in the absence of previously diagnosed family members, are often not recognised as being associated with Fabry disease. Recent research has shown increased psychosocial impact among patients whose severe clinical symptoms, such as acroparaesthesia, fatigue and heat intolerance, were either dismissed or misdiagnosed.4 Early diagnosis of Fabry disease is crucial to patient health and well-being and may help to avoid unnecessary interventions and anxiety in both patients and their carers. Timelier diagnosis may be aided by increased awareness of this disorder and the signs and symptoms that may present in early childhood. It is noteworthy that all three of the cases discussed in this paper initially presented with acroparaesthesia. In a recent evaluation of 30 Fabry disease patients, six were females who had symptom onset during childhood (ages 3–11 years); acroparaesthesia was among the presenting symptoms in all six of these cases.4 Neuropathic pain experienced by young patients with Fabry disease manifests as chronic acroparaesthesia superimposed by acute attacks of Fabry pain crisis. These symptoms reflect damage to small fibres in the peripheral and autonomic nervous systems as a result of accumulation of glycosphingolipids.8 Acroparaesthesia is often described by patients as a chronic, nagging, tingling, burning sensation in the hands and feet, while a pain crisis is an episode of acute, agonising pain, typically beginning in the extremities and radiating inward. The pain is typically precipitated by rapid changes in core body temperature (due to fever, illness, stress or exercise), sudden exposure to

Journal of Paediatrics and Child Health 51 (2015) 369–372 © 2014 The Author Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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Table 2

Fabry disease misdiagnosis and delay

Possible signs of Fabry disease in children

Neurological

Gastrointestinal tract

Opthalmological

Dermatological

Renal Cardiac Musculoskeletal Other

Acroparaesthesia Unexplained neuropathic pain Persistent ‘growing pains’ Early atypical multiple sclerosis (no oligoclonal bands) Recurrent unexplained headaches Recurrent vertigo Episodic non-inflammatory/non-infectious diarrhoea Unexplained recurrent abdominal pain/discomfort and/or vomiting Unexplained constipation Vortex keratopathy (cornea verticillata; Fig. 1) Cataract Conjunctival vessel dilatation/tortuosity Angiokeratoma Reduced sweating Heat intolerance Unexplained microalbuminuria/ proteinuria Left ventricular hypertrophy Exercise intolerance Fatigue Recurrent unexplained fever Depression

cold, changes in humidity or fatigue. Fabry pain crises may also manifest as acute abdominal pain. Other symptoms related to dysfunction of the autonomic nervous system observed in Fabry patients include hypohidrosis (decreased ability to sweat), impaired tear and saliva production, impaired gastrointestinal motility and sensory losses.9 Table 2 provides a comprehensive summary of possible symptoms that a paediatric patient may present with. Physicians should be particularly vigilant for persistent or recurrent symptoms. If a paediatric patient, male or female, presents with any of these symptoms, Fabry disease should be considered in the differential diagnosis. Early diagnosis can be significantly enhanced by taking a detailed medical and family history with emphasis on gaining insight into some of the non-specific presenting symptoms. Discussions with patients and their families about their pain should include onset, duration, distribution, intensity, abnormal responses to stimuli and triggering factors. Changes in bowel habits, including abdominal pain, post-prandial diarrhoea, nausea, vomiting, cramping and bloating should be discussed and documented. It is important to explore any patients who present with a history of abnormal sweating and intolerance to heat, cold and exercise, in particular those who also display a low level of tolerance for physical exertion, tiring or becoming overheated even after mild activity. It should be borne in mind that in children, angiokeratoma and characteristic vortex keratopathy, if present, may be the only physical findings. The Fabry-Specific Paediatric Health and Pain Questionnaire (FPHPQ) has, to date, been used to aid in assessing commonly reported symptoms experienced by children with Fabry disease

who are being followed in the Fabry Outcome Survey.10 Preliminary validation of the tool has demonstrated a potential 23-item structure for assessing three key symptom areas: pain associated with heat/exertion, pain associated with cold and abdominal pain/fatigue symptoms. It is anticipated that further refinement may lead to the development of a shorter screening instrument to help detect typical symptoms of Fabry disease. It is important to take family history regarding renal, cardiac and neurological disease and early deaths when Fabry disease is suspected. Difficulties often arise in making a diagnosis when no male index case is present. Early referral to a genetic metabolic physician is important to circumvent the need for further unnecessary evaluations and aid in determining a definitive diagnosis of Fabry disease. Genetic counselling and cascade testing can then be offered to at-risk family members. Specific treatment with enzyme replacement therapy is available for Fabry disease. Enzyme replacement therapy reduces levels of Gb3 in plasma, urine and tissues and can reduce symptom severity, improve pain-related quality of life and slow disease progression.11 The overall goal of enzyme replacement therapy in adults is to prevent further disease progression and, potentially, reverse underlying pathologic abnormalities. However, delayed diagnosis may lead to irreversible organ damage and reduced treatment efficacy.12 A definitive diagnosis ensures patients have early access to optimal monitoring, supportive management and appropriate treatment in order to prevent irreversible life-threatening complications. Fabry disease is a progressive disorder; in younger patients, the use of enzyme replacement therapy therefore focuses on disease prevention, where it has the potential to provide greater long-term benefits than in adults. Progressive podocyte injury has been associated with the development of renal complications in children with Fabry disease.13 Recent data demonstrate a significant correlation between dose of enzyme replacement therapy and reduction in Gb3 podocyte inclusions after longterm treatment in young patients.14 The same study showed complete clearance of Gb3 in mesangial and glomerular endothelial cells in all patients after 5 years of enzyme replacement therapy, irrespective of dose. Clinical trials with up to 4 years’ follow-up have established that the use of enzyme replacement therapy in children is well tolerated, reduces pain and improves pain-related quality of life.15–17 However, due to its high cost, the timing of access to enzyme replacement therapy continues to be guided predominantly by country-specific treatment criteria. In Australia there are eligibility criteria for males and females, with treatment initiated only after demonstration of the onset of clinically significant signs or symptoms. Earlier access, before irreversible organ dysfunction, should be considered. However, longerterm follow-up studies are needed to define a ‘window of opportunity’ within which early initiation of enzyme replacement therapy during childhood can prevent future organ damage.14

Conclusion Physicians should be familiar with signs and symptoms of Fabry disease in childhood. Fabry disease should be considered in the differential diagnosis when a young female patient presents

Journal of Paediatrics and Child Health 51 (2015) 369–372 © 2014 The Author Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

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with unusual or non-specific but recurrent or episodic symptoms, particularly unexplained neuropathic pain, exercise intolerability, fatigue and hypohidrosis.

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Acknowledgements The author acknowledges editorial assistance provided by Hazel Palmer of Scius Solutions Pty Ltd. Ms Palmer’s contribution was funded by Genzyme Australia Pty Ltd.

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2006; 1–18. Available from http://www.ncbi.nlm.nih.gov/books/ NBK11591/ Burlina AP, Sims KB, Politei JM et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 2011; 11: 61. Kolodny EH, Pastores GM. Anderson–Fabry disease: extrarenal, neurologic manifestations. J. Am. Soc. Nephrol. 2002; 13 (Suppl. 2): S150–3. Ramaswami U, Stull DE, Parini R et al. Measuring patient experiences in Fabry disease: validation of the Fabry-Specific Pediatric Health and Pain Questionnaire (FPHPQ). Health Qual. Life Outcomes 2012; 10: 116. doi:10.1186/1477-7525-10-116. Alegra T, Vairo F, de Souza MV, Krug BC, Schwartz IV. Enzyme replacement therapy for Fabry disease: a systematic review and meta-analysis. Genet. Mol. Biol. 2012; 35 (Suppl. 4): 947–54. Banikazemi M, Bultas J, Waldek S et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann. Intern. Med. 2007; 146: 77–86. Najafian B, Mauer M, Hopkin RJ, Svarstad E. Renal complications of Fabry disease in children. Pediatr. Nephrol. 2013; 28: 679–87. Tondel C, Bostad L, Larsen KK et al. Agalsidase benefits renal histology in young patients with Fabry disease. J. Am. Soc. Nephrol. 2013; 24: 137–48. Borgwardt L, Feldt-Rasmussen U, Rasmussen AK, Ballegaard M, Meldgaard LA. Fabry disease in children: agalsidase-beta enzyme replacement therapy. Clin. Genet. 2013; 83: 432–8. Ramaswami U. Update on role of agalsidase alfa in management of Fabry disease. Drug Des. Devel. Ther. 2011; 5: 155–73. Ramaswami U, Parini R, Pintos-Morell G, Kalkum G, Kampmann C, Beck M. Fabry disease in children and response to enzyme replacement therapy: results from the Fabry Outcome Survey. Clin. Genet. 2012; 81: 485–90.

Journal of Paediatrics and Child Health 51 (2015) 369–372 © 2014 The Author Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)

Diagnostic dilemma and delay in Fabry disease: insights from a case series of young female patients.

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