Rare Diseases

Neurofibromatosis (NF) is a set of genetic diseases that cause tumors to grow along various nerves and additionally affect the development of non-nervous tissues such as bone and skin. NF causes tumors to grow anywhere in the body. It also leads to developmental abnormalities.

Neurofibromatosis 1 (NF1), also known as von Recklinghausen NF or peripheral NF, occurs once in 4000 births. It is characterized by Café au lait spots on the skin and subcutaneous neurofibromas. Widening and deformity of the bones and curvature of the spine (scoliosis) may also occur. Rarely, tumors may develop inside the brain, in cranial nerves or in the spinal cord. Neurofibromatosis 2 (NF2), also known as bilateral acoustic NF (BAN), is rarer, occurring once in 40,000 births. NF2 is characterized by multiple tumors in cranial and spinal nerves and other lesions of the brain and spinal cord. Tumors affecting both hearing nerves are its distinctive sign. Hearing loss appearing in the teens to early twenties is usually the first symptom.

Duchenne Muscular Dystrophy (DMD) is the most common disease among muscle diseases. Since it occurs due to deletions in the dystrophin gene on the X chromosome, it is seen in one in 3500 male births. In this disease, a basic protein necessary for muscle function is missing.

In the absence of this protein, the muscles gradually weaken, and adipose tissue replaces muscle tissue. It is often diagnosed between the ages of 2-5. In DMD, weakness beginning in the muscles around the hips and shoulders progresses gradually; as a result of the weakening of the abdominal and back muscles, children walk with their abdomen pushed forward. As weakness in the leg muscles progresses, they fall frequently, have difficulty getting up from the ground and climbing stairs, and lose the ability to walk between the ages of 9-11 on average, starting to use a wheelchair. After this stage, the arm muscles also gradually weaken and the child has difficulty using their arms.

Cystic fibrosis (CF) is examined by whole gene sequencing.

This disease most commonly causes spots (hamartoma / a type of benign tumor) in all organs, especially the skin, brain and kidneys. Some symptoms are absent when the baby is born and appear later. For example, while it shows symptoms in the heart immediately at birth, kidney symptoms tend to appear after adolescence.

Lysosomal diseases are a group of hereditary diseases affecting tens of thousands of people worldwide. The majority of patients are predominantly children. A child with a lysosomal disease is born every half hour. As with other hereditary diseases, these diseases are passed from parents to children.

Although mucopolysaccharidoses result from disorders in different genes, they all share a common feature except MPS type II. Transmission in the genes occurs in an autosomal recessive inheritance pattern. That is, for the disease to appear in the child, the defect causing the disease must be present in the genes coming from both the mother and the father.

Neuro-cardio-facio-cutaneous diseases (RASopathies) are a group of diseases involving the nervous system, cardiovascular system and skin, causing dysmorphic facial features and exhibiting certain combinations of common and distinguishing clinical features. Noonan, LEOPARD, cardio-facio-cutaneous, Costello and Legius syndromes, and neurofibromatosis type 1 are among the diseases in this group.

Noonan syndrome (NS) is a genetically multisystemic disease, autosomal dominant, with a reported prevalence of approximately 1/2500. NS is clinically and genetically heterogeneous (it has different phenotypes). Approximately 50% of cases have a family history. The rate of de novo mutations is high. PTPN11 gene mutations are responsible for 50% of cases, SOS1 gene for 10-13%, and RAF1 gene for 3-17%.

Type 1 GSD is the clinically most severe type. Type 1-A results from glucose-6-phosphatase (G6PC) deficiency. Type 3 (AGL gene) is clinically similar to type 1 but has a milder course. Patients present in infancy with hypoglycemia, acidosis, growth retardation and hepatomegaly. In types 6 and 9, isolated hepatomegaly is usually seen without distinct clinical findings. Especially in type 1, hepatocellular adenomas may develop in patients over 10 years of age.

The type 2 GAA gene is located at locus 17q25.2-q25.3. The GAA gene encodes the enzyme called acid alpha glucosidase. Mutations in this gene cause Pompe disease.

Hypertrophic cardiomyopathy is a familial (autosomal dominant) disease with a wide spectrum of symptoms ranging from asymptomatic to loss of consciousness and fainting spells. It manifests itself with symptoms such as shortness of breath, palpitations, dizziness, inability to climb stairs, chest pains, back and leg pain, murmurs and labored breathing.

While in some patients the first sign is a rhythm disorder, there may sometimes be a risk of sudden cardiac arrest and death. Since the risk of sudden death is higher in childhood, early diagnosis of hypertrophic cardiomyopathy is much more important.

Long QT syndrome is a rare disease characterized by a myocardial repolarization disorder, not accompanied by structural cardiac anomaly, in which the risk of sudden infant death is increased. The frequency of congenital long QT syndrome is estimated at 1/2500-7000.

Disorders of glycosylation are inherited conditions that affect many parts of the body. Individuals with a disorder of glycosylation typically develop signs and symptoms of the condition during infancy. They may have difficulty gaining weight and growing at the expected rate (failure to thrive). Affected babies often have weak muscle tone (hypotonia) and developmental delay.

They may have seizures, problems with coordination and balance (ataxia), or stroke-like episodes involving extreme lack of energy (lethargy) and temporary paralysis. They may also develop blood clotting problems. Some individuals may have eye abnormalities, including eyes that do not look in the same direction (strabismus) and an eye disorder called Retinitis Pigmentosa that causes vision loss.

Women with disorders of glycosylation have hypergonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, most women with disorders of glycosylation do not go through puberty.

In general, the frequency of hearing loss has been determined as one in 1000 live births. About half of this figure is due to genetic causes and the other half to environmental causes. Autosomal recessive inheritance accounts for approximately 80% in the non-syndromic group.

Autosomal dominant and X-linked inheritance patterns are detected in 15-20% and 1-2% of cases, respectively. The place of mitochondrial inheritance within non-syndromic hearing loss varies between 1% and 20% depending on ethnic groups.

Most of the 30 mutations known so far are located in exon 10. Phenotypic differences in the disease are related to mutations, which is why genotype-phenotype correlation is being intensively studied. Codon 148, 680 and 694 mutations are important. Codon 680 and 694 mutations are associated with the disease.

Carriers of the M694V mutation show the disease at an earlier age and carry a serious risk for amyloidosis. In carriers of the V726A mutation, the risk of amyloidosis is lower. The E148Q mutation is associated with the mildest phenotype. Although mutations causing FMF disease are frequently seen in exons 2 and 10 of the MEFV gene, recent full exon sequencing has shown that pathogenic mutations can be seen in many regions of the gene.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disease (inherited autosomal dominant or recessive) characterized by obesity, retinal dystrophy, polydactyly, renal malformations, mental retardation and hypogonadism. Mutations in the BBS1 gene have been associated with Bardet-Biedl syndrome Type 1, mutations in the BBS2 gene with Type 2, and mutations in the BBS10 gene with Type 10.

Limb Girdle Muscular Dystrophy is a disease inherited in an autosomal dominant pattern. This type of the disease develops after mutations occurring in the MYOT, LMNA, CAV3 and DNAJB6 genes, which encode skeletal muscle proteins. Limb Girdle Muscular Dystrophy has been associated with more than one gene and has many types.

Spinocerebellar ataxia (SCA) is a disease in which imbalance is observed as a result of the loss or inability to function correctly of balance-related cells in the cerebellum and spinal cord. The typical sign of SCAs is imbalance. SCA1, SCA2, SCA3, SCA6 and SCA7 are the subtypes of the disease expressed by numbers. SCAs inherited in an autosomal dominant pattern occur through an increase in the number of CAG trinucleotide repeats in the relevant genes.

Alport Syndrome is a disease inherited autosomal recessive, autosomal dominant or X-linked recessive. The COL4A3, COL4A4 and COL4A5 genes have been associated with the disease. X-linked inherited COL4A5 mutations have been observed in 80% of patients.

Kallmann syndrome is one of the important causes of male infertility. It is seen together with hypogonadotropic hypogonadism and anosmia (inability to smell). Losses and changes in the KAL1 gene located at Xp22.3 cause the disease. In patients suspected of Kallmann disease, FISH analysis is performed to detect the Xp22.3 deletion.

Premature ovarian failure (POF) is a condition characterized by amenorrhea developing secondarily to the impairment of ovarian functions before the age of 40, elevated gonadotropin levels and consequently decreased blood estrogen levels, and the physiological and psychological problems this situation causes.

Primary ovarian failure is a condition that occurs in women under 40 with a 4-month amenorrhea process, a serum follicle-stimulating hormone (FSH) value higher than 40 IU/L measured one month apart, and a decrease in sex steroids. In women, menopause occurs between the ages of 40 and 60, with an average of 51.

Although the frequency of premature ovarian failure varies between populations, it affects approximately 1% of women under 40, approximately 0.1% of women under 30, and 0.01% of women under 20. In spontaneous 46,XX POF cases, it is necessary to share with patients the information that remissions and pregnancies may occur at a rate of 5-10%.

The most common genetic cause is chromosomal anomalies and mutations in the FMR1 gene on the X chromosome, which is responsible for Fragile-X syndrome. FSHB shows an autosomal recessive inheritance pattern. It shows features such as delayed bone age, infertility, low FSH and primordial follicles. The FSHR gene is autosomal dominant inherited. It is characterized by abdominal pain, nausea, enlarged multi-ovular ovaries and osteoporosis.

The main causes of male infertility are major chromosomal anomalies, Y chromosome microdeletions, cystic fibrosis, hormonal disorders and some rare genetic syndromes. Y chromosome microdeletions are located in the AZF region of the sequences on the Y chromosome.

AZFa: sY86, sY625, M259 / AZFb: sY131, sY127, sY134 / AZFc: sY255, sY157, sY254 — control: ZFY/ZFX, sY14 (SRY), sY81, sY90

In cystic fibrosis patients, cyclic AMP cannot be secreted out of epithelial cells. As a result of this condition, excess salt in sweat, chronic lung diseases and pancreatic failure emerge. 97-98% of men with cystic fibrosis have azoospermia due to bilateral congenital absence of the vas deferens (CBAVD).

In addition, it is stated that female patients may experience fertility problems due to deterioration in cervical mucus quality. Meconium ileus develops in 10-20% of newborns with cystic fibrosis due to the accumulation of thickened meconium in the distal intestine. It is a single-gene disease inherited autosomal recessive. In our laboratory, whole gene DNA sequencing of the CFTR gene is performed.

Familial Mediterranean Fever: It is a genetically inherited (autosomal recessive) disease with recurrent attacks of fever, abdominal pain (peritonitis), chest pain (pleuritis), joint pain and swelling (arthritis), and rarely heart membrane (pericarditis) and meningitis (brain membrane involvement) attacks.

The mutations causing the disease are frequently located in exons 2 and 10 of the gene. For diagnosis, it is recommended to analyze, in order of mutation frequency, exon 2 and exon 10 (Step 1); then exons 3 and 5 DNA sequencing (Step 2); and if no disease-associated change is detected, whole gene DNA sequencing (Step 3). In our laboratory, Step 3 is not proceeded to without studying Steps 1 and 2 MEFV DNA sequencing.

In individuals with the c.35delG mutation in the GJB2 gene, hearing loss is observed within and between families. Hearing loss, with an incidence of 1-2 in 1000 newborns, is the most common sensory disorder in societies. The degree of hearing loss can vary from very mild to very advanced, and it can also vary between unilateral or bilateral.

According to the cause of occurrence, hearing losses are classified as genetic and environmental. Today, it is known that mutations in more than 70 genes result in hearing loss.

Fragile X Syndrome is the most common hereditary cause of intellectual disability and learning difficulties. The increase in CGG repeats in the FMR1 gene on the X chromosome is responsible for Fragile X syndrome. Epilepsy also accompanies one quarter of people with the disease.