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Rare and Genetic Metabolic Diseases

Rare diseases are those that affect a small number of individuals compared to the general population.

According to the definition by the European Union (EU), a disease is considered rare when it affects 5 out of 10,000 people in the community.¹
It is estimated that in Greece, approximately 350,000 to 600,000 people are affected by rare diseases, and over 30 million people in Europe.²
In total, there have been around 6,000 to 8,000 rare diseases recorded globally. Of these, 72% are genetic, while others result from infections, cancers, allergies, and environmental factors. To this day, the cause of many rare diseases remains unknown^3,4

Rare and Genetic Metabolic Diseases

Rare diseases are those that affect a small number of individuals compared to the general population.

For many rare diseases, signs and symptoms may be observed at birth or in childhood, however, over 50% of rare diseases appear during adulthood.

Common symptoms can sometimes mask underlying rare diseases, leading to misdiagnosis and treatment delays.⁴
Therefore, while these conditions may differ, they all present similar clinical challenges, since many healthcare professionals may lack experience in recognizing or managing the majority of rare diseases. As a result, diagnosis is often delayed or inaccurate, making optimal clinical management more difficult.⁵

Sources

https://eody.gov.gr/disease/spania-nosimata/
https://rarediseasesgreece.gr/
https://www.eurordis.org/
https://www.orpha.net/
Haendel M, Vasilevsky N, Unni D, Bologa C, Harris N, Rehm H, Hamosh A, Baynam G, Groza T, McMurry J, Dawkins H, Rath A, Thaxon C, Bocci G, Joachimiak MP, Köhler S, Robinson PN, Mungall C, Oprea TI. How many rare diseases are there? Nat Rev Drug Discov. 2020 Feb;19(2):77-78. doi: 10.1038/d41573-019-00180-y. PMID: 32020066; PMCID: PMC7771654.)

Polyneuropathy in Hereditary

Transthyretin Amyloidosis
(hATTR)

Hereditary transthyretin amyloidosis (hATTR) is a rare hereditary disorder caused by mutations in the gene responsible for the expression of the transthyretin protein (TTR).

Familial Chylomicronemia
	Syndrome (FCS) Familial Chylomicronemia Syndrome (FCS) is a rare hereditary disorder with an estimated prevalence of 1/1,000,000 in the population, although it is possibly under-recognized and under-diagnosed.¹


Familial Chylomicronemia
	Syndrome (FCS) Familial Chylomicronemia Syndrome (FCS) is a rare hereditary disorder with an estimated prevalence of 1/1,000,000 in the population, although it is possibly under-recognized and under-diagnosed.¹ Read More It is characterized by the loss of lipoprotein lipase activity, resulting in the accumulation of chylomicrons in the plasma and significantly elevated triglyceride levels, 10 to 100 times higher than normal.^1,2 The increased triglycerides lead to several complications in patients, with the most severe being recurrent episodes of acute pancreatitis, a potentially life-threatening complication. Therefore, identifying patients with FCS for the administration of appropriate treatment that would mitigate the risk of acute pancreatitis is extremely important. Sources (Ueda M. Familial chylomicronemia syndrome: importance of diagnostic vigilance. Transl Pediatr. 2022 Oct;11(10):1588-1594. doi: 10.21037/tp-22-488. PMID: 36345451; PMCID: PMC9636463) Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, Yang Q, Hughes SG, Geary RS, Arca M, Stroes ESG, Bergeron J, Soran H, Civeira F, Hemphill L, Tsimikas S, Blom DJ, O’Dea L, Bruckert E. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 2019 Aug 8;381(6):531-542. doi: 10.1056/ NEJMoa1715944. PMID: 31390500)

Mucopolysaccharidosis Type VII

(MPS VII or Sly Syndrome)

Mucopolysaccharidosis Type VII (MPS VII) is an ultra rare, heterogeneous, progressive neuro-metabolic disorder caused by a deficiency of the lysosomal enzyme β-glucuronidase^1,2.

Long-Chain

Fatty Acid Oxidation Disorders (LC-FAODs)

Fatty acid oxidation disorders (FAODs) are a group of rare diseases with an autosomal recessive inheritance pattern and are associated with significant morbidity and mortality¹.

Alagille
	Syndrome (ALGS) Alagille Syndrome is a rare genetic disorder with an incidence of 1:30,000-50,000¹. It is an autosomal dominant condition, meaning that children of a patient with Alagille Syndrome have a 50% chance of being affected.

Alagille Syndrome is caused by mutations in certain genes (JAG1 or NOTCH2), resulting in defective bile duct formation within the liver and abnormalities in skeletal, ocular, cardiovascular, and renal development². The lack of bile ducts, a hallmark of ALGS, leads to reduced bile flow, accumulation of bile acids, and cholestatic liver damage.

Around 40% of patients inherit the mutation from their parents, while 60% have de novo mutations³.

Symptoms of Alagille Syndrome appear at birth and include jaundiced skin and intense itching^4,5. The cholestatic itching caused by ALGS is the most severe of any liver disease⁶. Other symptoms involve various systems, such as the skeletal system (Butterfly vertebrae, characteristic facial features with a prominent forehead, deep-set eyes, and a pointed chin), the cardiovascular system (pulmonary stenosis, Tetralogy of Fallot), hearing loss, ocular disorders (posterior embryotoxon), and renal issues (dysplasia, renal tubular acidosis)^1,5,7. Xanthomas (fat deposits on extending surfaces resulting from increased cholesterol) also affect 30-42% of patients^5,8.

When Alagille Syndrome is suspected in a newborn or infant with cholestasis, jaundice, and morphological or other clinical findings, a comprehensive laboratory evaluation is performed to confirm the diagnosis. If the diagnosis is not established, but clinical findings suggest ALGS, the patient may undergo genetic testing^3,8.

Diagnosing ALGS is challenging due to the fact that its symptoms could be attributed to other equally rare diseases, such as intrahepatic cholestasis or progressive familial intrahepatic cholestasis. Unnecessary surgery could worsen the course of the disease⁹.

ALGS leads to progressive liver failure, with 24% – 42% of patients surviving without liver transplantation up to the age of 18.5¹⁰ years. Cardiovascular complications are a significant cause of morbidity and mortality not only in children but also in adult patients with ALGS, who need to be identified and managed as early as possible.

ALGS is a multisystem disorder that requires an interdisciplinary team of specialized pediatricians and pathologists for effective management and ensuring long-term survival along with a good quality of life for these fragile patients¹¹.

Eur J Hum Genet 2014; 22.
J Hepatol 2016; 65:631–642.
Diagnostics 2020; 10:907–924.
Med Sci Monit 2014; 20:476–480;
J Pediatr Gastroenterol Nutr 2018; 67:148–156;
J Pediatr Gastroenterol Nutr 2010; 51:759–765;
Eur J Hum Genet 2012; 20:251–257.
Appl Clin Genet 2016;9:75-82
International Liver Congress (EASL), 2020
Kamath BM, et al. Hepatol Comms 2020; 4:387–398.
J Multidiscip Healthc. 2022; 15: 353–364.


Alagille
	Syndrome (ALGS) Alagille Syndrome is a rare genetic disorder with an incidence of 1:30,000-50,000¹. It is an autosomal dominant condition, meaning that children of a patient with Alagille Syndrome have a 50% chance of being affected. Read More Alagille Syndrome is caused by mutations in certain genes (JAG1 or NOTCH2), resulting in defective bile duct formation within the liver and abnormalities in skeletal, ocular, cardiovascular, and renal development². The lack of bile ducts, a hallmark of ALGS, leads to reduced bile flow, accumulation of bile acids, and cholestatic liver damage. Around 40% of patients inherit the mutation from their parents, while 60% have de novo mutations³. Symptoms of Alagille Syndrome appear at birth and include jaundiced skin and intense itching^4,5. The cholestatic itching caused by ALGS is the most severe of any liver disease⁶. Other symptoms involve various systems, such as the skeletal system (Butterfly vertebrae, characteristic facial features with a prominent forehead, deep-set eyes, and a pointed chin), the cardiovascular system (pulmonary stenosis, Tetralogy of Fallot), hearing loss, ocular disorders (posterior embryotoxon), and renal issues (dysplasia, renal tubular acidosis)^1,5,7. Xanthomas (fat deposits on extending surfaces resulting from increased cholesterol) also affect 30-42% of patients^5,8. When Alagille Syndrome is suspected in a newborn or infant with cholestasis, jaundice, and morphological or other clinical findings, a comprehensive laboratory evaluation is performed to confirm the diagnosis. If the diagnosis is not established, but clinical findings suggest ALGS, the patient may undergo genetic testing^3,8. Diagnosing ALGS is challenging due to the fact that its symptoms could be attributed to other equally rare diseases, such as intrahepatic cholestasis or progressive familial intrahepatic cholestasis. Unnecessary surgery could worsen the course of the disease⁹. ALGS leads to progressive liver failure, with 24% – 42% of patients surviving without liver transplantation up to the age of 18.5¹⁰ years. Cardiovascular complications are a significant cause of morbidity and mortality not only in children but also in adult patients with ALGS, who need to be identified and managed as early as possible. ALGS is a multisystem disorder that requires an interdisciplinary team of specialized pediatricians and pathologists for effective management and ensuring long-term survival along with a good quality of life for these fragile patients¹¹. Eur J Hum Genet 2014; 22. J Hepatol 2016; 65:631–642. Diagnostics 2020; 10:907–924. Med Sci Monit 2014; 20:476–480; J Pediatr Gastroenterol Nutr 2018; 67:148–156; J Pediatr Gastroenterol Nutr 2010; 51:759–765; Eur J Hum Genet 2012; 20:251–257. Appl Clin Genet 2016;9:75-82 International Liver Congress (EASL), 2020 Kamath BM, et al. Hepatol Comms 2020; 4:387–398. J Multidiscip Healthc. 2022; 15: 353–364.


Wilson’s Disease Wilson’s Disease (WD), formerly known as hepatolenticular degeneration, is a rare inherited genetic disorder, inherited in an autosomal recessive manner.


Wilson’s Disease
	Wilson’s Disease (WD), formerly known as hepatolenticular degeneration, is a rare inherited genetic disorder, inherited in an autosomal recessive manner. Read More It is caused by mutations in the ATP7B gene, which encodes a transmembrane copper transport protein, disrupting its function and leading to the accumulation of copper in the liver, brain, and other vital organs.¹ The usual age of onset is between 4-40 years, although cases as young as 3 years and as old as 70 years have been reported in the literature. ² The clinical course can vary in terms of the type and severity of symptoms, but progressive liver disease is a common feature. Patients may also present with neurological and psychiatric symptoms, as well as ophthalmological manifestations such as Kayser-Fleischer rings. Guidelines recommend that in any patient with unexplained liver function abnormalities, especially when associated with neurological or psychiatric disorders, the possibility of Wilson’s disease should be considered.³ If the diagnosis is confirmed, treatment is lifelong. Sources Członkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML. Wilson disease. Nat Rev Dis Primers. 2018 Sep 6;4(1):21. doi: 10.1038/s41572-018-0018-3. PMID: 30190489; PMCID: PMC6416051 Alkhouri N, Gonzalez-Peralta RP, Medici V. Wilson disease: a summary of the updated AASLD Practice Guidance. Hepatol Commun. 2023 May 15;7(6):e0150. doi: 10.1097/HC9.0000000000000150. PMID: 37184530; PMCID: PMC10187853 Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology. 2022 Dec 7. doi: 10.1002/hep.32801. Epub ahead of print. PMID: 36151586.

Congenital

Adrenal
Hyperplasia

Congenital Adrenal Hyperplasia (CAH) comprises a group of disorders resulting from the deficiency of one of the enzymes involved in the synthesis of cortisol, a hormone produced in the adrenal glands. CAH is inherited in an autosomal recessive manner¹.

The deficiency of cortisol leads to an increase in ACTH (adrenocorticotropic hormone), which is secreted by the pituitary gland. This, in turn, results in the hyperplasia (overgrowth) of the adrenal glands, leading to a wide range of clinical manifestations².

The most common cause of CAH is a deficiency in the 21-hydroxylase enzyme, which is present in approximately 90% of cases³.

Conventionally, the deficiency of the 21-hydroxylase enzyme is classified into classical and non-classical forms. The classical form can be further categorized into “salt-wasting” and “simple virilizing” subtypes⁴.

The clinical symptoms of the disease depend on the type of CAH, the severity of the enzyme deficiency, and the gender of the patient. Patients with salt-wasting CAH typically present from neonatal or early infancy with symptoms like poor weight gain, vomiting, dehydration, and hyperkalemia. Female individuals with CAH may exhibit ambiguous genitalia or virilization, even prenatally, due to their exposure to high levels of adrenal androgens caused by adrenal gland hyperplasia. Other symptoms may include growth delay, delayed puberty, infertility, hirsutism, and features of a metabolic syndrome.^5,6

Diagnosis of CAH can be made at birth by implementing newborn screening for metabolic disorders in a private context. At present, testing for CAH is not included in the diseases screened in national Newborn Screening Programs. In cases where newborn screening is not available and there are clinical findings suggestive of CAH, measurements of 17-hydroxyprogesterone, which are typically very high immediately after birth, especially in the classical form of 21-hydroxylase deficiency, may be conducted. As part of the evaluation, serum electrolyte measurements, other hormone assays to identify the specific enzyme deficiency, and, if necessary, a cosyntropin stimulation test (ACTH stimulation test) may be performed. Genetic testing is not always deemed necessary for diagnosis, except when the results of the other testing methods are inconclusive or if genetic counseling is needed⁷.

The management of CAH includes achieving three primary clinical objectives: the replacement of cortisol (and aldosterone if required), reducing exposure to high levels of adrenal androgens based on the patient’s age and gender, and avoiding overtreatment with its associated complications⁸.

Sources

J Clin Endocrinol Metab, March 2008, 93(3):653– 660.
J Steroid Biochem Mol Biol. 2015 Sep; 153: 63–71.
N Engl J Med.2003;349:776–788.
Endocrinol Metab Clin North Am. 2015 Jun; 44(2): 275–296.
Seminars in reproductive medicine. 2012 Oct;30(5):400–409.
J Clin Endocrinol Metab. 2010 Nov; 95(11): 5110–5121.
Eur J Hum Genet. 2020;28(10):1341.
J. Clin. Endocrinol. Metab. 2013, 98, 2645–2655.

Adrenal
	Insufficiency Adrenal insufficiency is a rare condition that can develop over time and, less commonly, can present as an acute, potentially life-threatening condition called an adrenal crisis. The most common cause of adrenal insufficiency is the abrupt discontinuation of corticosteroid therapy after prolonged treatment.

It is classified into:

Primary (Addison’s Disease): In this type, the adrenal glands lose their ability to produce the hormones for which they are responsible. Unless there are co-existing factors such as infections, tumors, or bleeding disorders of the adrenal glands, the disease is autoimmune. In developed countries, about 8-9 out of 10 cases of Addison’s disease have an autoimmune origin. Its approximate incidence is 100-140 individuals per million¹.
Secondary and Tertiary (or Central Type): In these types, the inability to produce adrenal hormones is due to inadequate secretion of necessary hormones by the pituitary gland (corticotropin, ACTH), or the hypothalamus (corticotropin-releasing hormone, CRH) of the brain, respectively. The hypothalamus, pituitary, and adrenal glands form an axis called the “hypothalamic-pituitary-adrenal (HPA) axis” that regulates the production of adrenal hormones. Damage to the hypothalamus or pituitary from local causes (tumors, bleeding disorders) or systemic causes (infections, genetic disorders) can disrupt the functioning of the HPA axis, leading to adrenal insufficiency. Central adrenal insufficiency is more common, affecting 150-280 individuals per million^2,3

The symptoms of adrenal insufficiency are nonspecific, making diagnosis challenging. Common symptoms include fatigue, weakness, anorexia, and weight loss, which can be seen in both types of adrenal insufficiency. In Addison’s disease, skin hyperpigmentation, gastrointestinal symptoms like nausea and vomiting may also occur. Other symptoms may include dizziness, myalgias, and arthralgias⁴

The diagnosis of adrenal insufficiency can be made by measuring morning cortisol and ACTH levels, and it can be confirmed with an ACTH stimulation test. To determine the underlying cause of adrenal insufficiency, the treating physician may also test for autoantibodies against 21-hydroxylase. Depending on the results, imaging of the brain might be necessary⁵

The treatment of adrenal insufficiency is based on adequate replacement of cortisol and any other deficient adrenal hormones to prevent an adrenal crisis.

Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers. Long-term studies in the last decade have shown increased mortality, morbidity, and reduced quality of life in patients with adrenal insufficiency. These findings are at least partially attributed to the failure of cortisol replacement therapy to mimic the normal circadian rhythm of cortisol secretion⁶.

The Journal of Clinical Endocrinology and Metabolism. 2016;101(2):364–369.
Annals of Endocrinology (Paris). 2017;78(6):490–494.
Lancet. 2014;383(9935):2152–2167.
https://www.uptodate.com/contents/adrenal-insufficiency-beyond-the-basics
J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.
Lancet Diabetes Endocrinol 2015; 3: 216–26


Adrenal
	Insufficiency Adrenal insufficiency is a rare condition that can develop over time and, less commonly, can present as an acute, potentially life-threatening condition called an adrenal crisis. The most common cause of adrenal insufficiency is the abrupt discontinuation of corticosteroid therapy after prolonged treatment. Read More It is classified into: Primary (Addison’s Disease): In this type, the adrenal glands lose their ability to produce the hormones for which they are responsible. Unless there are co-existing factors such as infections, tumors, or bleeding disorders of the adrenal glands, the disease is autoimmune. In developed countries, about 8-9 out of 10 cases of Addison’s disease have an autoimmune origin. Its approximate incidence is 100-140 individuals per million¹. Secondary and Tertiary (or Central Type): In these types, the inability to produce adrenal hormones is due to inadequate secretion of necessary hormones by the pituitary gland (corticotropin, ACTH), or the hypothalamus (corticotropin-releasing hormone, CRH) of the brain, respectively. The hypothalamus, pituitary, and adrenal glands form an axis called the “hypothalamic-pituitary-adrenal (HPA) axis” that regulates the production of adrenal hormones. Damage to the hypothalamus or pituitary from local causes (tumors, bleeding disorders) or systemic causes (infections, genetic disorders) can disrupt the functioning of the HPA axis, leading to adrenal insufficiency. Central adrenal insufficiency is more common, affecting 150-280 individuals per million^2,3 The symptoms of adrenal insufficiency are nonspecific, making diagnosis challenging. Common symptoms include fatigue, weakness, anorexia, and weight loss, which can be seen in both types of adrenal insufficiency. In Addison’s disease, skin hyperpigmentation, gastrointestinal symptoms like nausea and vomiting may also occur. Other symptoms may include dizziness, myalgias, and arthralgias⁴ The diagnosis of adrenal insufficiency can be made by measuring morning cortisol and ACTH levels, and it can be confirmed with an ACTH stimulation test. To determine the underlying cause of adrenal insufficiency, the treating physician may also test for autoantibodies against 21-hydroxylase. Depending on the results, imaging of the brain might be necessary⁵ The treatment of adrenal insufficiency is based on adequate replacement of cortisol and any other deficient adrenal hormones to prevent an adrenal crisis. Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers. Long-term studies in the last decade have shown increased mortality, morbidity, and reduced quality of life in patients with adrenal insufficiency. These findings are at least partially attributed to the failure of cortisol replacement therapy to mimic the normal circadian rhythm of cortisol secretion⁶. The Journal of Clinical Endocrinology and Metabolism. 2016;101(2):364–369. Annals of Endocrinology (Paris). 2017;78(6):490–494. Lancet. 2014;383(9935):2152–2167. https://www.uptodate.com/contents/adrenal-insufficiency-beyond-the-basics J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. Lancet Diabetes Endocrinol 2015; 3: 216–26

Severe Sialorrhea

in chronic neurological disorders

Sialorrhea is defined as the overproduction or inability to control saliva beyond the boundaries of the lips¹. It is a symptom that is evaluated after the age of 36 months, at which point it is considered that full control of the oral cavity has been achieved.

This information is intended for public awareness purposes only and, under no circumstances, can it replace the advice of a doctor or another qualified healthcare professional.

Therapeutic

Areas

Oncology

Hematology

Rare and Genetic
Metabolic Diseases

Wound

Care

Oncology

Hematology

Rare and Genetic
Metabolic Diseases

Wound

Care

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