Metabolic Disorders/ IEM

Metabolic disorders/IEMs are caused when the body is unable to break down nutrients, which then accumulate in the body and becomes toxic.

When the concentration of toxic build-up increase they cross

the blood-brain barrier and this leads to delayed development, brain damage and, in some cases, even death.

Most infants with these disorders show no obvious signs of

these disorders at birth, but the build-up can be rapid enough for the condition to become irreversible within a few weeks of birth.

Reason behind these Disorders

These disorders follow an autosomal recessive inheritance pattern

Could skip generations

Parents are carriers

Happens when the two parents carry the gene 1:4 probability of having an affected child

Early detection is very important

Affected babies are identified quickly before symptoms appear.

Cases of disease are not missed.

The number of false-positive results is minimized.

Early treatment can begin, that prevents the negative and irreversible health outcomes for affected newborns.

Most treatments are inexpensive and may involve the addition of a vitamin to the diet, hormone supplementation, avoidance of certain foods and chemicals or a dietary change.

INBORN ERROR OF MEATBOLISM DEFINATION :

Rare group of recessive genetic disorders in which the body can not metabolize food components normally . These disorders are usually caused by defects in enzymes involved in the biochemical pathways that break down food components .

S P

C

Toxic substrate accumulation

Activate different pathways

Alternative pathway

Diversion to second

pathways

Product deficiency

Barriers to Newborn Screening

Cost of the screening and treatment Test cannot be done at birth (birth has to be in a hospital) Insufficient sampling due to the lack of proper training and education Difficult to reach in different geographic location Problems with recall and follow up cases

If screening is delayed

It could lead to lifelong complications:

Mental Retardation

Motor Impairment

Physical Disability

GA 1 Screened

GA 1 Not Screened

GA 1 Screened

Newborn tested 48-72 Hours after birth

Confirmatory Test

Start Treatment

Positive

Negative

Positive

The newborn screen has to be done only once in a lifetime Speeds diagnosis and saves costs Healthy child instead of sick or mentally retarded child.

Negative

Benefits of Newborn Screening for Metabolic Disorders

Anytime 24 hours AFTER birth (ideally within 48-72 hrs).

Baby needs to be fed at least 2 - 3 times before the specimen is taken.

BEFORE developmental delay or other symptoms of mental retardation occur (best time is to screen a healthy baby).

Time to do screening

Every Newborn (Routine screening) High Risk

Unexplained deaths of siblings Miscarriages & Aborted Fetuses Exhibit symptoms of IEMs Babies conceived by IVF Babies in NICU

Sick Children

13

Every Newborn needs to be Screened

Sample from baby’s Heel

1. Puncture heel 2. Lightly touch filter paper to LARGE blood drop

3. Dry the sample & send to the laboratory

Tandem Mass Spectrometry (MS/MS)

Mass Spectrometry means multiple analyte testing Using Tandem Mass Spectrometry, multiple analytes are measured

simultaneously Quantitatively measures amino acids and acylcarnitines from dried blood

spot specimens Efficient and Economical MS/MS is very precise

Expanded Newborn Screening

ACYLCARNITINE PROFILE (Tandem Mass Spectrometry)

I. Fatty Acid Oxidation Disorders

II. Organic Acid Disorders

AMINO ACID PROFILE (Tandem Mass Spectrometry)

I. Amino Acid Disorders

BIOCHEMICAL SCREENING (Enzyme Assay/Enz. immunoassay)

I. Galactosemia

II. Congenital Hypothyroidism

III. Congenital Adrenal Hyperplasia

IV. Biotinidase Deficiency

Test Amino Acidemias :

Phenylketonuria (PKU)

Maple syrup urine disease (MSUD)

Homocystinuria (Cystathionine synthase def.)

Citrullinemia (ASA synthase deficiency )

Tyrosinemia (Type 1)

Argininosuccinic Aciduria (ASA Lyase deficiency)

Organic Acidemias :

Propionic Acidemia (PA)

Methylmalonic Acidemia (MMA)

Isovaleric Acidemia (IVA)

Glutaric Acidemia Type I (GA-I)

3-methylcrotonyl-CoA Carboxylase deficiency (3MCC)

Beta Ketothiolase deficiency (Mitochondrial Acetoacetyl CoA

Thiolase deficiency)

Multiple CoA Carboxylase deficiency (MCD)

Fatty Acid Oxidation Defect :

Medium Chain Acyl CoA Dehydrogenase Deficiency (MCAD)

Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCAD)

Long Chain Hydroxy Acyl Dehydrogenase (LCHAD)

Trifunctional Protein Deficiency (TFP)

3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency (3HMG)

Galactosemia

Biotinidase Deficiency

Endocrine Disorders :

Congenital Hypothyrodism

Congenital Adrenal Hyperplasia

Amino Acid (AA) Disorders

• Most common AA disorder—PKU—is part of the current test panel

• Expansion added additional 6 AA disorders

• All are recessive genetic disorders so risk of recurrence is 1:4 with each pregnancy

• Symptoms and treatments vary by disorder

Phenylketonuria (PKU) • Caused by a lack of the enzyme Phenylalanine

Hydroxylase . If not treated, this disease causes irreversible mental retardation from an early stage as a result of a buidup of phenylalanine in the blood. Prevalence within the Arab world 1:2,500.

المرض هذا سبب phenylalanine Hydroxylase أنزم نمص •

االولى المراحل خالل عالجه تم لم اذا للشفاء لابل ؼر عمل تخلؾ نسبة , الدم phenylalanine تراكم نتجة وهذا , الطفل عمر من

. 1:2,500 العرب العالم ف المرض انتشار

Maple Syrup Urine Disease (MSUD) • Caused by a lack of the Branched –chain Alpha-Keto

Acid Dehydrogenase complex (BCKDH), which in turn leads to a buildup of Leucine,Isoleucine and Valine in the blood. If untreated ,the disorder causes vomiting,dehydration,seizures and brain damage . The Classic Severe MSUD form of the disease is fatal . Prevalence is roughly 1:80,000 .

Branched –chain Alpha-Keto Acid أنزم نمص سببه•

Dehydrogenase complex (BCKDH) تراكم ف تسبب الذي . الدم ف Leucine,Isoleucine and Valine االمنة االحماض

ارادة ال وحركات وجفاؾ تمؤ سبب االختالل هذا عالج ل الكالسك بشكله MSUD مرض أن . الدماغ ف تلؾ و بالعضالت

1:80,000 تمربا انتشاره نسبة . الوفاة ال ؤدي الحاد

Homocysteinuria • Caused by a lack of the enzyme Cystathionine B-

Synthase that leads to buildup of Methionine since Homocysteine is not being converted into Cysteine . Methionine buildup leads to connective tissue, muscle ,CNS and cardiovascular damage . Prevalence about 1:3,000

الى ؤدي الذي Cystathionine B-Synthase انزم نمص سببه• ال Homocysteine تحول عدم بسبب Methionine تراكم

Cysteine . تراكم Methionine الضام النسج تلؾ ال ؤدي . الدموي واالوعة والملب المركزي العصب والجهاز والعضالت

. 1:3000 ال المرض هذا انتشار نسبة وتصل

Citrullinemia (Argininosuccinic Synthetase Deficiency )

• There are two types of this disorder, Citrullinemia Type I is caused by a lack of the enzyme Argininosuccic synthetase, which converts citrulline and aspartate into argininosuccinate, and is the third step in the urea cycle. Citrullinemia Type II is caused by a defect in Citrin, which is responsible for the transport of molecules across the mitochondrial membrane. In its absence, the urea cycle fails to function properly. Symptoms include vomiting, loss of consciousness, seizures, failure to thrive as a result of the buildup of ammonia within the blood, abnormal behavior and confusion. Prevalence of Type I is 1:57,000. Prevalence of Type II is 1:250,000. •

Argininosuccinic سببه نمص أنزم Citrullinemia Type I :وجد نوعان من هذا المرض•Synthetase الذي حول Citrulline وAspartate إلى Argininosuccinate هو ,

المسؤول عن Citrin, سببه خلل ف Citrullinemia Type II الخطوة الثالثة ف دورة الورانمل الجزئات عبر ؼشاء الماتوكوندرا, حث أن دورة الورا ال تعمل بشكل صحح ف عدم

تتضمن األعراض تمؤ وفمدان الوع وحركات ال إرادة ف العضالت واضطراب ف .وجوده النمو نتجة لتراكم األمونا ف الدم والسلون الؽر طبع واالرتبان, نسبة انتشار النوع األول1:57,000

. 1:250,000 ونسبة انتشار النوع الثان•

Tyrosinemia Type I • Sometimes referred to as Richner-Hanhart Syndrome,

this disorder is caused by a lack of the enzyme Tyrosine Aminotransferase. It is the first step in the metabolism of tyrosine. Symptoms range from death within 12 months if not treated to impaired muscle movement a later stage in life. Prevalence worldwide stands at around 1:250,000.

هو , Fumarylacetoacetate Hydrolase أنزم نمص سببه• تتراوح Tyrosine ل األضة العملة ف األخرة الخطوة

إلى )عالجه تم لم إذا شهرا 12 ال خالل( الوفاة بن ما األعراض نسبة تمدر .الحاة من الحك ولت ف العضالت حركة ف ضعؾ 1:100,000 ب عالما المرض هذا حدوث

Fatty Acid Oxidation Disorders (FAODS)

Most common FA disorder—MCADD—is part of the current test panel

Expansion added eleven FAO disorders

Most are autosomal recessive disorders so risk of recurrence is 1:4 with each pregnancy

Symptoms of Fatty Acid Oxidation Disorders

– Hypoketotic hypoglycemia

– Muscle weakness

– Seizures

– Sometimes cardiomyopathy

Treatment of most Fatty Acid Oxidation Disorders

– Avoid fasting – Immediate medical attention when unable to eat

usual diet – Control type/amount of fat in diet depending upon

the specific diagnosis – L-Carnitine if indicated – Cornstarch tube feeding at night if indicated

Argininosuccinic Aciduria • Caused by a lack of the enzyme Argininosuccinate

Lyase which in turn prevents the conversion of argininosuccinate into arginine. Symptoms of the disorder include vomiting, nausea, seizures, coma and damage to the nervous system. Milder forms of the disease only present symptoms during the onset of a secondary disease. Prevalence is roughly 1:70,000.

عدم ف تسبب الذي Arginosuccinate Lyase أنزم نمص سببه• هذا أعراض تتضمن Arginine. إلى Argininosuccinate تحول

وتلؾ وؼبوبة العضالت ف إرادة ال وحركات وؼثان تمؤ اإلختالل لهذا المتوسط الشكل ف األعراض تظهر وال العصب, الجهاز ف

فتبلػ انتشاره نسبة أما .آخر مرض ألي المصاب تعرض إذا إال المرض . 1:70,000 حوال

3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency (3HMG)

• Caused by a lack of the enzyme 3-Hydroxy-3-Methylglutaryl-CoA Lyase which plays a role in the breakdown of the amin acid leucine . symptoms include vomiting , dehydration , lethargy , convulsion and coma . It is a rare disorder.

Hydroxy-3-Methylglutaryl-CoA-3 أنزم نمص سببه•Lyase االمن الحمض تكسر ف رئسا دورا لعب الذي

leucine و وتشنجات سباتا و جفافا و تمؤا األعراض تتضمن نادر االختالل هذا و ؼبوبة

Trifunctional Protein Deficiency • As the name suggests , it is a complex formed by three

enzymes coded for by two genes responsible for the breakdown of fatty acids within the mitochondria. A mutation in either gene causes trifunctional protein deficiency . Symptoms include lack of energy , low blood sugar , heart problems , breathing difficulties and sudden death . It ia arare disorder

طرك عن مشفرة أنزمات ثالثة من تكون مركب خو االسم وح كما• ف الدهنة االحماض تكسر عن المسؤولة الجنات من اثنن

نمص ال ؤدي الجنات هذة احد ف ط . الماتوكوندراtrifunctional protein و الطالة ف نمصا االعراض تتضمن حث

و التنفس ف صعوبة و الملب ف مشاكل و الدم ف السكر نسبة انخفاض نادرا االختالل هذا عتب و مفاجئا موتا

Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD)

• Caused by a lack of the enzyme Very Long Chain Acyl-CoA Dehydrogenase which is responsible for the breakdown of very long chain fatty acids within the mitochondria for energy production. Symptoms include a lack of energy , low blood sugar, heart problems,breathing difficulties , liver problems and sudden death . it is a rare disorder .

Very Long Chain Acyl-CoA Dehydrogenase انزم نمص سببه• داخل جدا الطولة السلسلة ذات الدهنة االحماض تكسر عن المسؤول

و الطالة ف نمصا االعراض تتضمن , الطالة إلنتاج وذلن , المتوكوندرا و التنفس ف وصعوبة الملب ف مشاكل و الدم ف السكر نسبة انخفاض . نادر االختالل هذا عتبر و , مفاجئا موتا و الكبد ف مشاكل

Long Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency (LCHADD) • Caused by a lack of the enzyme Long Chain 3-Hydroxy

Acyl-CoA Dehydrogenase which is responsible for the breakdown of long chain fatty acids within the mitochondria for energy production . Symptoms include a lack of energy , low blood sugar , heart problems, breathing difficulties , liver problems and sudden death . It is a rare disorder .

Long Chain 3-Hydroxy Acyl-CoA أنزم نمص سببه•Dehydrogenase ذات الدهنة االحماض تكسر عن المسؤول

, الطالة إلنتاج وذلن , الماتوكوندرا داخل جدا الطولة السلسلة و الدم ف السكر نسبة انخفاض و الطالة ف نمصا االعراض تتضمن مفاجئا موتا و الكبد ف ومشاكل التنفس ف صعوبة و الملب ف مشاكل

. نادرا االختالل هذا عتبر و

Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)

• Caused by lack of the enzyme Medium Chain Acyl-CoA Dehydrogenase which is responsible for the breakdown of medium chain fatty acids within the mitochondria for energy production , symptoms include a lack of energy , low blood sugar , heart problems , breathing difficulties , liver problems and sudden death . prevalence is roughly 1:15,000

Medium Chain Acyl-CoA Dehydrogenase انزم نمص سببه• داخل جدا الطولة السلسلة ذات الدهنة االحماض تكسر عن المسؤول

الطالة ف نمصا األعراض تتضمن , الطالة إلنتاج ذلن و الماتوكوندرا التنفس ف صعوبة و الملب ف مشاكل و الدم ف السكر نسبة وانخفاض 1:15,000 تمربا انتشارة نسبة تبلػ و مفاجئا موتا و الكبد ف ومشاكل

Organic Acid (OA) Disorders

• Expansion added the detection of 16 organic acid disorders

• Most are autosomal recessive disorders so risk of recurrence is 1:4 with each pregnancy

• A few sub-types are X-linked so only males are affected, but females may show milder symptoms

Symptoms of most Organic Acid Disorders

– Feeding problems (feed intolerance)

– Seizures

– Metabolic acidosis

– Lethargy

Treatment of most Organic Acid Disorders

– Avoid fasting

– Immediate medical attention when unable to eat usual diet

– Control type/amount of protein in diet depending upon the specific diagnosis

– Vitamin B12 if indicated

Isovaleric Aciduria • Caused by a lack of the enzyme Isovaleric Acid-CoA

Dehydrogenase that plays a role in the breakdown of leucine , an essential amino acid . Symptoms include poor feeding , vomiting , seizures , lack of energy and comas . A distinctive odour of sweaty feet is also common .Prevalence is 1:250,000

الذي Isovaleric Acid-CoA Dehydrogenase انزم نمص سببه•

االمنة االحماض من هو و اللوسن تحطم عملة ف دورا لعب إرادة ال حركات و تمؤ و تؽذة سوء االعراض تتضمن , الرئسة

ممزة عرق رائحة و ؼبوبة و الطالة ف نمصا و العضالت ف 1:250,000 االختالل هذا انتشار ن .أضا شائعة للمدمن

Propionic Aciduria • Caused by a lack of the enzyme Propionyl-CoA

Carboxylase , which is responsible for the breakdown of a number of essential amino acids . Symptoms include seizures , vomiting and dehydration . The disorder can quickly become life threatening . Prevalence about 1:250,000 .

عن المسؤول Propionyl-CoA Carboxylase انزم نمص سببه•

االعراض تتضمن الرئسة األمنة االحماض من عدد تحطم

االختالل هذا هدد و جفافا و تمؤ و العضالت ف إرادة ال حركاتا 1:250.000 عالة انتشارة نسبة , سرعة بطرمة الحاة

Methylmalonic Aciduria • Caused by a lack of the enzyme Methylmalonyl-

CoA Mutase or as a result of Vitamin B12 metabolism deficiency . Symptoms include brain damage and hyperammonemia . prevalence is 1:50,000

كنتجة أو Methylmalonyl-CoA Mutase ان نمص سببه•

ف تلفا االعراض تتضمن 12 ب فتامن ف االض لنمص

1:50,000 انتشارة نسبة تبلػ و االمونا ف زادة و الدماغ

Glutaric Aciduria Type I • Caused by a lack of the enzyme Glutaryl-CoA

Carboxylase , which is responsible for the breakdown of number of essential amino acids . baby born with this disorder exhibit a large head , spasms , rigidity and bleeding from the brain . Prevalence is 1:30,000

عن المسؤول Glutaryl-CoA Carboxylase انزم نمص سببه•

االعراض تتضمن , الرئسة االمنة االحماض من عدد تحطم

الدماغ ف نزؾ و صالبة و تشنجات و كبر برأس طفل والدة 1:30000 انتشارة نسبة تبلػ و

B-ketothiolase Deficiency • Caused by a lack of the enzyme B-Ketothiolase

which plays an essential role in the breakdown of the amino acid isoleucine .Symptoms include vomiting , dehydration , trouble breathing , extreme tiredness , convulsion and comas .It is arare disorder .

ف رئسا دورا لعب الذي B-Ketothiolase انزم نمص سببه•

و تمؤ االعراض تتضمن و ازلوسن األمن الحمض تكسر

و تشنجات و شددا تعبا و التنفس ف صعوبة و جفافؾ . نادر االختالل هذا و ؼبوبة

3-methylcrotonyl-CoA Carboxylase Deficiency

• Caused by a lack of the enzyme 3Methylcrotonyl-CoA Carboxylase which plays an essential role in the breakdown of amino acid leucine .Symptoms include lethargy ,delayed development and coma . prevalence is 1:50,000.

3Methylcrotonyl-CoA Carboxylase انزم نمص سببه• و لوسن االمن الحمض تكسر ف رئسا دورا لعب الذي

تبلػ و ؼبوبة و النمو ف تاخر و السبات االعراض تتضمن 1:50,000 انتشارة نسبة

Multiple –CoA Carboxylase Deficiency

• Caused by a lack of any four different CoA Carboxylase enzyme . Multiple CoA Carboxylase Deficency can be associated with biotinadse deficiency . Symptoms include lethargy , poor feeding , seizures and coma .I is arare disorder .

هذا CoA Carboxylase انزمات أربعة من واحد نمص سببه• االعراض تتضمن و biotinades نمص مع ترافك االختالل ؼبوبة و العضالت ف ارادة ال وحركات تؽذة سوء و السبات

نادر االختالل هذا و

Congenital Adrenal Hyperplasia (17-Hydroxyprogesterone )

• Caused by a lack of the enzyme 21-Hydroxylase , which

plays a vital role in the synthesis of cortisol and aldosterone . Symptoms include early puberty , stunted growth and wrong gender assignment and in its most severe form can lead to death . Prevalence world wide 1:25,000

Hydroxylase-21 انزم نمص بسبب الخلم الكظرة الؽدة تضخم• وتمضن االلدوسترون و الكورتزول تصنع ف حوا دورا لعب الذي

ؤدي و الطفل و جنس تمز و عدم و تمزم و المبكر البلوغ االعراض 1:25,000 انتشاره نسبة تبلػ الوفاة إل حاالتة أشد ف

Classic Galactosemia

• Caused by a lack of the enzyme Galactose-1-phosphouridyl transferase which prevent the body from properly breaking down galactose into glucose . Symptoms include liver , kidney and brain damage . prevelance is 1:50,000

Galactose-1-phosphouridylسببه نمص انزم •transferase ؤدي نمصة ال عدم لدرة الجسم على تكسر

الجالكتوز ال جلوكوز وتتضمن األعراض تدمر الكبد 1:50,000والكل والدماغ و تبلػ نسبة انتشارة

Congenital Hypothyroidism (TSH) • Caused primarily by an abnormal thyroid gland or a

mutation in the receptors or hormones produced to help thyroid gland function . Symptoms include poor growth and development and mental retardation if untreated . prevalence is 1:4,000

أو طبعة ؼر درلة ؼدة الرئس سببه – الخلم الدرلة الؽدة نشاط •

المحفزة الهرومونات انتاج ف أو الؽدة هرمونات مستمبالت ف طفرة

تخلفا و النمو ف تاخر و اعالة االعراض تتضمن و الدرلة للؽدة 1:4,000 انتشارة نسبة تبلػ و مبكر بشكل عالج لم واذا عملا

If diagnosed treatment is easy

just thyroid hormone for life

Biotindase deficiency • Biotinidase deficiency is unable to recycle the vitamin

biotin., can cause seizures, weak muscle tone (hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis. Affected children also have delayed development. Lifelong treatment can prevent these complications from occurring or improve them if they have already developed.

البوتن فتامن مع التعامل على المدرة ففمد البوتندز انزم نمص سببه• فمدان و التنفس ف صعوبة و العضالت ف ضعؾ و تشنجات ف ممتسبب

االصابة و للشعر فمدان و جلدة حساسة و المش صعوبة و والبصر السمع مدى العالج ال طبع بشكل لعش الطفل حتاج و النمو تاخر و بالفطرات

الحاة

Conclusion

All babies have equal right to live healthy lives

&

We need to create the platform for them