Tag Archives: #raregeneticdiseases

Medium Chain ActylCoA Dehydrogenase Deficiency (MCAD)

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, Life Sciences GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Medium Chain ActylCoA Dehydrogenase Deficiency (MCAD) prevents converting fats to energy especially with fasting fatty acids → acetylCoA). MCAD is inherited in an autosomal recessive manner (25% if both parents are gene carriers).

MCAD is characterized by:

  • Vomiting
  • Lethargy
  • Seizures
  • Hypoglycemia

A mutation may be found in the ACADM gene.

Inheritance: 1 in 50,000

Diagnosis: 

  • Pregnancy – HELLP

Fatty Acid Oxidation Deficiency. Diagnosis: blood/urine (blood – acylcantiines (alanocylcarnitines)

Rx: Glucose – avoid starvation L carnitine?

Medicine: Ravicti

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease.

National Organization of Rare Diseases was established in 1983 by Abbey Meyers and others.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome [e.g. Medium Chain AcylCoA Dehydrogenase Deficiency (MCAD)] and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background.

With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required. 

Neurofibromatosis

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Neurofibromatosis) and the family wants to know from the healthcare provider:

Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers)

Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family

Whether there is testing for the disease and/or syndrome

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background.

With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

Case Study: We received a phone call from a new mother who found out she has one affected newborn twin with Neurofibromatosis and the other twin is unaffected. Since there was no known history of Neurofibromatosis on either mother or father’s side of the family the family was unprepared for the diagnosis.

Neurofibromatosis Type 1 (NF1) is characterized by small or large usually benign tumors of the nerves and connective tissue in the skin and/or other organs. Patients usually have freckling on the armpits and groin and multiple brownish (café-au-lait) spots on the skin. The gene is found on chromosome #17q11.2

Neurofibromatosis Type 1 (NF2) is characterized by benign tumors which develop on the 8th nerve causing dizziness, balance problems, ringing in the ears and deafness. The gene is found on chromosome #22q12.2.

Inheritance: Risk may approach 50% if inherited in an autosomal dominant manner. Autosomal dominant diseases caused by a mutation in a single gene characteristically are variable in onset and severity. Neurofibromatosis can be caused by a new mutation in that individual and subsequently that individual will have a 50% chance of passing the new mutation to a child causing the disease.

Incidence of a new mutation as a cause for this disease is approximately 50%. 50% of cases are transmitted from a carrier parent who may or may not be aware of the presence of the disease.

  • NF1 (17q11.2) – Occurrence 1 in 3000 births – Approximate number of gene mutations, more than 1000
  • NF2 (22q12.2) – Occurrence 1 in 25,000 births – Approximate number of gene mutations, at least 200

http://www.nfnetwork.org/

Approximate Risks to a Child if the Affected Individual is:

  • Grandparent/Second Degree Relative: Risk should be less than 12.5% that a child will be affected
  • Parent/First Degree Relative: Risk should be less than 25% that a child will be affected
  • Mother/Father/Sibling: Risk may approach 50% that a child will be affected

**Patient should be made aware that no DNA screening is 100% reliable. The risk for being a carrier of the disease is reduced by testing, but no DNA laboratory will declare an individual to be a “non-carrier” due to unknown mutations.

Analysis: Due to the large number of mutations, DNA testing by gene sequencing is NOT performed routinely for Neurofibromatosis unless a known mutation has been identified in an affected relative.

Neonatology – Chromosome Testing vs Exome Testing

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital                                                                                                       

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in their lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases was established in 1983 by Abbey Meyers and others.

Analysis: One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers), multifactorial (interaction of multiple genes with the environment, both genetic and non-genetic factors)?
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family?
  • Whether the disease is caused by a Microdeletion?
  • Whether there is testing for the disease and/or syndrome?
  • If there is testing, is prenatal diagnosis and/or Preimplantation Genetic Diagnosis (PGD) available?

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use.

However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background. With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase. Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

Background: There are over 500 conditions that have been implicated in Autism, Intellectual or Developmental Disabilities.

  • Routine Chromosome Studies will detect 3-5% of patients with Autism, Developmental Disabilities or Intellectual Disabilities
  • Fragile X testing is important especially in males (2-4% of males have Autism, Developmental Disabilities or Intellectual Disabilities 1-2% of females)
  • Other X Linked gene mutations
  • Rett Syndrome (X Linked in Girls) 0-4.4% – Average 1.5%: MECP2 gene, CDKL5 gene
  • Inborn Errors of Metabolism 1-5% cause Autism, Developmental Disabilities or Intellectual Disabilities

Exome Microarray:

  • 35% have a copy number variation (CNV’s)
  • 40% of CNV’s are new (de novo)
  • 14% of these patients have Autism, Developmental Disabilities or Intellectual Disabilities
  • 10% clear association with Autism, Developmental Disabilities or Intellectual Disabilities

14 major regions identified and correlated with Autism, Developmental Disabilities or Intellectual Disabilities.

Brain (Neuroimaging) 6-48% depending on severity of condition.

Other Causes: Prematurity, Spina Bifida, Cerebral Palsy, Infection.

If Chromosomal Microarray detects an unusual variant which is considered significant (up to 45 known at present):

  1. Approximately 20 are associated with heart problems
  2. Approximately 14 are associated with vision or hearing problems
  3. Approximately 6 are associated with seizures
  4. Approximately 5 are associated with kidney problems
  5. Approximately 2 are associated with blood disorder

What is the difference between chromosomal testing and exome testing?

  • The exome includes the protein coding genes
  • There are 23 pairs of chromosomes, 22 pairs of autosomes and 2 sex chromosomes. 2X’s in a normal female (usual female) and 1X and 1Y in a normal male (usual male)   

What is the Exome? The protein forming genes in an individual.

What is the Genome? Complete set of genes or genetic material in an individual.

Blood Leukocyte Karyotyping: Culture of circulating WBC’s in the blood of an individual, stopping the growth of the cells when they are dividing, exploding the cells and staining and matching the individual chromosomes. Examining the number, integrity and intactness of each chromosome, looking for an increased or decreased number and the gain or loss or exchange of chromosomal material. There are 22 pairs of autosomes, 1 from each parent, 2X chromosomes in the usual female and 1X and 1Y chromosome in the usual male.

*Chromosomal Microarray: Is evaluation of the components of the individual chromosomes, evaluating small additions or deletions of chromosomal material not identified by microscopic evaluation of chromosomes. Variations in the number of copies of DNA within a sequence are common and gains or losses may be associated with a disorder or increased or decreased susceptibility to a disorder e.g. CGG repeats in Fragile X. *First test considered for Autism, Developmental Disabilities or Intellectual Disabilities

Next Generation Sequencing (NGS): or High Throughput Sequencing: Term used to described several different types of sequencing DNA or RNA segments more quickly and economically. At the present time, is generally considered “experimental” in an individual.

 

Rare Genetic Diseases – Fried Syndrome

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people or less. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

Analysis:: Fried Syndrome: Is a sex (X) linked disorder (50% of males will be affected, 50% of females will be carriers) associated with a mutation at the p22 locus of the X chromosome.

  • Prevalence is not known but is believed to be less than 1 in 1,000,000 births.

Fried Syndrome results in:

  • Facial changes
  • Developmental delay
  • Hydrocephalus
  • Calcification of the basal ganglia
  • Spastic diplegia

Mutations in the AP1S2 gene have been described. Mutations in this gene are also associated with mal-development of the middle portion of the cerebellum with an enlargement of the 4th ventricle of the brain (Dandy-Walker Syndrome).

One of the greatest dilemmas facing the healthcare provider is when a family presents with a positive family history of a very rare genetic disease and/or syndrome (e.g. Fried Syndrome) and the family wants to know from the healthcare provider:

  • Whether the disease and/or syndrome is inherited (autosomal dominant manner (50%), autosomal recessive (25% if both parents are gene carriers) or sex (X) linked (50% of males will be affected, 50% of females will be carriers)
  • Whether the disease and/or syndrome is sporadic (due to a new mutation) and might or might not reoccur in a family
  • Whether there is testing for the disease and/or syndrome

Furthermore, if screening and/or testing is available, the healthcare provider has the responsibility of deciding whether to recommend testing which may or may not detect patients who are carriers or affected with one or more disorders.

If a test returns as “carrier” most conditions identified will require testing the partner since the majority of the conditions tested for are inherited in an autosomal recessive manner [inheritance of one disease causing (deleterious) gene from each parent].

Since not all screening laboratories are contracted with insurance companies and panels currently offered may screen from 3 to 250 diseases, the healthcare provider will need to decide which tests to order and which laboratory to use. However, the ACOG guideline does not set up a specific pre pregnancy panel nor recommend how many diseases or which diseases should be tested for except for those already recommended [e.g. Cystic Fibrosis, Fragile X, Spinal Muscular Atrophy (SMA), some “ethnic” panels, etc.].

Some laboratories are now offering “customized” panels developed by the healthcare provider in consultation with the laboratory based on the individual’s personal and family history and background.

With the increasing availability of such panels and the reduction in the cost, the demand for larger panels and the need for interpretation of laboratory results for the healthcare provider and the patient will continue to increase.

Likewise, it can also be expected as the number of diseases tested for increases, a greater percentage of “variants of uncertain clinical significance” will also increase.  Interpretation, explanation and additional recommendations for monitoring and follow-up of the individual screened and other family members will also be required.

*A recent study, that is ongoing, has suggested a possible relationship between maternal age (35 years or older) and/or paternal age (greater than 40 years) and autism and/or autism spectrum disorder(s) in a child. Reference: Israel & Mt. Sinai, NY.  *Some recent studies have suggested risk may be as high as 1:50 to 1:80.

Epilepsy – Early Infantile Encephalopathy (EIEE)

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: It is estimated that there are between 4,000 and 20,000 diseases (with over 7000 rare genetic diseases) and several companies are offering screening panels for the carrier state of several hundred conditions and the possible predisposition for various cancers including some hematologic and neurologic malignancies.

Rare Disease affects 1 in 2000 people. 7% of the population will be affected with a rare disease in the lifetime.

Rare Genetic Disease affects 1 in 200,000 people. The registry established that there are an average of 4200 cases per Rare Disease. National Organization of Rare Diseases established 1983 by Abbey Meyers and others got Orphan Drug Act passed 1983.

Analysis:  Epilepsy – Early Infantile Encephalopathy (EIEE) which has a prevalence of approximately 1 in 50,000 to 1 in 100,000.

The diagnosis of Epilepsy – Early Infantile Encephalopathy (EIEE) represents a diagnostic dilemma for the clinician as the symptoms overlap several other syndromes; some more amenable to treatment than others.

The presentation of epilepsy in combination with multiple other symptoms and as a component of many syndromes with or without encephalopathy represents a diagnostic dilemma.

There are multiple panels which are available to evaluate gene mutations including STXBP1 gene mutations which might provide a definitive diagnosis.

Epilepsy panels looking at 53 or 65 genes or larger panels studying 189 genes are often ordered to include the STXBPI gene which may have as many as 85 mutations to explain the multiple symptoms and variable severity.

Included in many of the panels are mutations which help diagnose:

  • West Syndrome
  • Lennox Gaustaut Syndrome
  • Dravet Syndrome
  • Rett Syndrome or Atypical Rett Syndrome
  • Ohtahara Syndrome

Treatable disorders often confused with STXBP1 mutations may include the following and others:

  • Pyridoxine-Dependent Epilepsy
  • Biotinidase Deficiency
  • Glucose Transporter 1 Deficiency
  • Holocarboxylase Synthetase Deficiency
  • Creatine Deficiency Syndromes
  • Serine Biosynthesis Disorders

Virtually all of the cases of STXBP1 have been sporadic with no family recurrence. The possibility of gonadal mosaicism exists posing a very small risk for recurrence.

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