metabolic disorders 1

Question 1

Describe the NBS (newborn blood spot or heel prick test) screening programme.

Answer 1

It includes screening for 9 conditions, such as Sickle cell disease, Cystic fibrosis, and Phenylketonuria, among others.

Question 2

What are some of the conditions included in the NBS screening programme since 2014?

Answer 2

Sickle cell disease (SCD), Cystic fibrosis (CF), Congenital hypothyroidism (CHT), Phenylketonuria (PKU), and more.

Question 3

Define Inherited metabolic diseases.

Answer 3

They are genetic diseases that affect metabolism, such as PKU, MCADD, MSUD, IVA, GA1, and HCU.

Question 4

How many babies born in the UK have PKU or MCADD?

Answer 4

About 1 in 10,000 babies born in the UK have PKU or MCADD.

Question 5

Describe Sever Combined Immunodeficiency (SCID).

Answer 5

It is a group of rare, inherited disorders causing major abnormalities of the immune system, usually due to the absence or malfunction of a necessary protein.

Question 6

What happens without treatment for babies with inherited metabolic diseases?

Answer 6

Babies can become suddenly and seriously ill, with different symptoms depending on the specific condition, which can be life-threatening or cause severe developmental problems.

Question 7

Describe the concept of screening for disease according to Wilson and Jungner.

Answer 7

Screening is the presumptive identification of unrecognized disease or defect through tests, examinations, or procedures that can be rapidly applied.

Question 8

What are the criteria that need to be fulfilled for a condition to be suitable for screening, as per Wilson and Jungner?

Answer 8

The condition should be an important health problem, have an accepted treatment, facilities for diagnosis and treatment available, a recognizable early stage, a suitable test acceptable to the population, understood natural history, agreed policy on treatment, economically balanced cost, continuous case finding, and resources for follow-up.

Question 9

How are inborn errors of metabolism typically treated?

Answer 9

They can be treated with a carefully managed diet and, in some cases, medication.

Question 10

Define familial hypercholesterolaemia (FH) in terms of its genetic basis.

Answer 10

It is an inherited defect in cholesterol/lipoprotein metabolism.

Question 11

What is the significance of MS-MS methods in the context of inborn errors of metabolism screening?

Answer 11

MS-MS methods, particularly tandem mass spectrometry, have contributed significantly to the technical advances in screening for these conditions.

Question 12

How does early disease detection and treatment contribute to combating diseases, according to Wilson and Jungner?

Answer 12

Early detection and treatment aim to bring undetected cases to treatment while avoiding harm to those who do not need treatment, although the path to successful achievement is complex.

Question 13

Describe the biochemical basis of conditions like PKU and MCADD.

Answer 13

The biochemical basis involves specific metabolic pathways that are affected in these conditions, leading to the accumulation of certain substances or the inability to break down others.

Question 14

What is the role of the NHS Screening Programme in relation to inborn errors of metabolism?

Answer 14

The NHS Screening Programme plays a crucial role in identifying and referring babies suspected of having these conditions for clinical care.

Question 15

How do inborn errors of metabolism fulfill the criteria for suitable screening conditions?

Answer 15

They fulfill the criteria by being important health problems with accepted treatments, available facilities, recognizable early stages, suitable tests, understood natural history, agreed treatment policies, balanced costs, continuous case finding, and resources for follow-up.

Question 16

What is the quote regarding the rarity of individual inborn errors of metabolism but their overall significance?

Answer 16

“Each individual inborn error of metabolism is rare but the total incidence is significant.”

Question 17

Describe the potential consequences if children with certain conditions are left undiosed and untreated.

Answer 17

Children may require hospitalization for extended periods, intensive care, and long-term institutional care, impacting both families and healthcare systems.

Question 18

Define the criteria that need to be met for a condition to considered suitable for newborn screening.

Answer 18

The condition must be an important health problem, have an accepted treatment, facilities for diagnosis and treatment available, a recognizable early stage, a suitable test, acceptable to the population, understood natural history, agreed policy on treatment, economically balanced case finding, and a continuous screening process.

Question 19

What is the Guthrie test and its significance?

Answer 19

The Guthrie test, also known as the ‘heel prick’ test, was established by Robert Guthrie in 1962. It was the original test for phenylketonuria (PKU) and used a bio-assay to test for phenylalanine, phenylpyruvate, and/or phenyllactate.

Question 20

How many conditions are currently included in the NHS newborn blood spot screening programme?

Answer 20

There are 9 conditions included in the programme since 2014, including sickle cell disease, cystic fibrosis, congenital hypothyroidism, inherited metabolic diseases, phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease, isovaleric acidemia, and glutaric aciduria type 1.

Question 21

Describe the effects of untreated thyroxine deficiency in congenital hypothyroidism.

Answer 21

Untreated thyroxine deficiency can lead to failure to thrive, delayed development, intellectual developmental disorders, infertility, and congenital iodine deficiency syndrome.

Question 22

What are some causes of congenital hypothyroidism?

Answer 22

Causes include lack of dietary iodine, complete absence of the thyroid gland, abnormal development of the thyroid gland, and rare genetic defects affecting thyroxine biosynthesis.

Question 23

Explain the process of thyroxine biosynthesis.

Answer 23

Thyroxine biosynthesis involves the absorption of iodine by the thyroid gland, which starts functioning around 20 weeks gestation. It can be affected by genetic causes such as mutations in the receptor for thyroid stimulating hormone, certain transcription factors, and mutations in proteins involved in thyroxine production like Na+/I- symporter, thyroglobulin, and thyroid peroxidase.

Question 24

Describe the process of thyroxine biosynthesis in the thyroid gland.

Answer 24

Throxine is produced through the uptake of iodine via the Na+/I- symporter, iodination of tyrosine residues in thyroglobulin, coupling of iodinated tyrosines, endocytosis, proteolysis, and secretion into circulation via monocarboxylate transporter.

Question 25

What is the function of thyroglobulin in the thyroid gland?

Answer 25

Thyroglobulin is a large glycosylated dimeric protein secreted from thyroid epithelial cells into the gland lumen, serving as a precursor for thyroid hormone synthesis.

Question 26

Define congenital hypothyroidism and its testing methods.

Answer 26

Congenital hypothyroidism is a condition present at birth due to thyroid hormone deficiency. Testing involves screening for TSH levels, immunoassays for free thyroxine, and assessing TSH response to thyroid hormone levels.

Question 27

How is levothyroxine used in the treatment of congenital hypothyroidism?

Answer 27

Levothyroxine, a synthetic form of T4, is administered orally to normalize TSH levels. The starting dose is typically 10-15 μg/kg/day, aiming to achieve TSH normalization within the first month of treatment.

Question 28

Describe Inborn Errors of Metabolism and provide examples of disorders tested at birth.

Answer 28

Inborn Errors of Metabolism are rare genetic diseases caused by enzyme deficiencies in metabolic pathways. Examples tested at birth include phenylketonuria, maple syrup urine disease, medium-chain acyl-CoA dehydrogenase deficiency, and others.

Question 29

Who is Sir Archibald Garrod and what is Alkaptonuria?

Answer 29

Sir Archibald Garrod linked hereditary traits to enzyme deficiencies, highlighting Alkaptonuria as the first disorder showing this relationship. Alkaptonuria involves the accumulation and excretion of homogentisic acid, leading to black urine.

Question 30

What is the role of thyroid peroxidase in thyroid hormone synthesis?

Answer 30

Thyroid peroxidase catalyzes the oxidation of iodide to iodine and the coupling of iodinated tyrosine residues in thyroglobulin to form thyroid hormones like thyroxine and triiodothyronine.

Question 31

How does T3 differ from T4 in terms of potency and production?

Answer 31

T3 is approximately 4 times more potent than T4 and is mostly produced through de-iodination processes. Both hormones play crucial roles in regulating metabolism.

Question 32

Explain the significance of iodination as an unusual post-translational modification in thyroid hormone synthesis.

Answer 32

Iodination of tyrosine residues in thyroglobulin is a unique post-translational modification essential for the production of thyroid hormones, distinguishing the thyroid gland’s function.

Question 33

What is the objective of treatment with levothyroxine in congenital hypothyroidism?

Answer 33

The goal of levothyroxine treatment is to normalize TSH levels within the first month, leading to the normalization of free T4 and a 50% reduction in TSH. Adjustments may be needed to maintain hormone levels.

Question 34

Describe the historical timeline of discoveries related to Alkaptonuria.

Answer 34

Predates “one gene, one enzyme” hypothesis (1941) and Vernon Ingram’s work on HbS (1958). Homogentisic acid oxidase deficiency (1958). Mutations identified in 1996.

Question 35

What is the breakdown pathway of Phenylalanine (Phe) and Tyrosine in Alkaptonuria?

Answer 35

It leads to acetoacetate and fumarate.

Question 36

Define Alkaptonuria and its consequences.

Answer 36

It is a condition where homogentisic acid is oxidized to BQA, which polymerizes and accumulates in tissues, potentially leading to cartilage damage and osteoarthritis.

Question 37

How did Garrod contribute to the understanding of Alkaptonuria?

Answer 37

He identified albinism as an Inherited Disorder of Metabolism (tyrosine 3-monooxygenase).

Question 38

What is the significance of newborn screening for inherited diseases like Alkaptonuria?

Answer 38

It allows for the early detection and treatment of rare conditions that can have profound consequences if left untreated, thus reducing the burden on the healthcare system.

Question 39

Do all the inherited diseases mentioned in the content have reliable detection and effective treatment options?

Answer 39

Yes, all can be reliably detected and treated very effectively and relatively easily.