Presentation1

Spectrum of IEM disease in Jeddah region

POINTS IN THE PRESENTATION

• 1-list of metabolic cases diagnosed or referred to the MCH from 2010-2013

• 2-their follow up and condition in the present time

• 3-presentation of rare metabolic cases

• 4-discussion of 2 relatively rare disorders of diagnosed cases

Inborn errors of metabolism (IEM) can be classified according to the size of

accumulated or deficient metabolites into small-molecule disorders such as

aminoacidemia, organic acidopathies, urea cycle defect, galactosemia, fatty acid

oxidation disorders, and other disorders such as glycogen and lysosomal storage

and organelle diseases.

small-molecule disorders

DISEASE CATOGRIES NUMBER OF CASES DIAGNOSED Number of deaths

PPA

IVA

B KETOTHYOLASE DEFECIENCY

MMA

PKU

TYROSENEMIA

MCAD

7

3

6

4

2

1

2

4

-

2

-

-

-

DISEASE CATOGRIES NUMBER OF CASES DIAGNOSED Number of deathes

GAU1

VLCAD

CPT1

NKH

UCD

HOMOCYSTINURIA

MSUD

5

2

1

2

3

1

6

-

-

-

-

2

-

-

DISEASE CATOGRIES NUMBER OF CASES DIAGNOSED Number of deaths

HMG COLYASE

3MCC DEFECEINCY

AMINOAYCLASE 1 DEFECIENCY

1

2

1

-

-

-

STOREGE DISORDERSDISEASE CATOGRIES NUMBER OF CASES

DIAGNOSEDNumber of deaths

MPS1

MPSVI

POMPE

GOUCHER DISEASE

3

4

2

2

-

-

1

-

CASESE 1

• 2 years old• Product of ClS• Neonatal jaundice• Elevated glturyl carnatine in

neonatal screening• Seen at my clinic at the age of 2 m• completely healthy with normal

examination of all body systems• Now at 2y of age , normal

development, no attacks of seizure, normal muscle tone and reflexes,

• Tandem ms done was normal

• Urine GC-MS showed –(2M)

Elevated N-acetylated amino acids

N-acetylmethyonine

N-acetylglutamic

N-acetylglycine

Test repeated after 5 months—same result

Result suggestive of Aminoacylase 1 deficiency

Aminoacylase 1 deficiency

• Aminoacylase (ACY1) is a zinc binding enzyme which hydrolyzes N-acetyl amino acids into the free amino acid and acetic acid

• Of the N-actyl amino hydrolyzing enzymes, aminoacylase 1 is the most common

• The ACY1 gene is located on the short arm of chromosome 3 (3p21.2).

• function as a tumor suppressor gene in small cell lung cancer and in renal carcinoma,

• may also play a role in monitoring responses to oxidative stress and in regulation of cellular red ox status.

The clinical picture

• heterogeneous

• motor delay, seizure, moderate to severe mental retardation, absent speech, growth delay, muscular hypotonia and autism ,autistic feature.

• It remains uncertain whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply biochemical variant.

• The organic acids analysis that led to thedetection of ACY1 deficiency is part of selective screening for inborn errors of metabolism, which is not performed routinely in healthychildren but only in individuals in whom a metabolic disease is considered, resulting in a strong bias

• However its expression in the central nervous system in human, suggested a role of the enzyme in the amino acid metabolism of these organ

• Van Coster et al. (2005) reported an infant with aminoacylase-1 deficiency presented neonatally with an acute encephalopathy with onset on the third day of life. Clinical features included seizures, apnea, vomiting, hypotonia, and sensorineural hearing loss.

• Urinalysis detected several N-acetylated amino acids.

• MRI showed cerebral atrophy. At age 9 months, he had reached normal developmental milestones and there were no abnormal clinical neurologic signs.

• Sass et al. (2006) presented 4 children with a genetic deficiency of ACY1 identified through organic acid analyses.

• The clinical phenotypes of the patients were heterogeneous:

• 1 subject-- nonspecific psychomotor delay • Second subject --psychomotor delay with atrophy of

the vermis and syringomyelia• in a third ---marked muscular hypotonia, • the fourth subject -- follow-up for early treated

biotinidase deficiency with normal clinical findings

• Sass et al. (2007) reported 3 additional patients with ACY1 deficiency detected through newborn screening

• Two patients were born of consanguineous parents of Asian and Romani origin, respectively. The Asian child presented with febrile seizures at 11 months of age, followed 3 months later by more seizures associated with a viral illness. She showed \delayed speech and language development at age 4 years.

• The Romani child had onset of multifocal, drug-resistant epilepsy with atonic, tonic, and absence seizures at age 1 year. He was hyperactive with moderate mental retardation.

• The third patient, of English origin, presented at 11 months with a prolonged generalized seizure and transient hemiplegia associated with illness. She showed complete recovery and normal development at age 19 months.

Case 2• Aseel 5years old female• SVD, APGAR 9/10/, BW=2.8KG• Newborn screening=increased of

C5-hydroxy acylcarnitine in blood

• increased 3 hydroxi isovalaric and3 methylCartonyl glycin in Urine

Developed one attack of decompansation,managed at her localhospital Referred to my clinic at the age of one

Month,

• Metabolic tests done Confirmed the diagnosis

3-Methylcrotonyl-CoA carboxylase deficiency(3MCC deficiency )

• Managed

• Diet- leucine free formula- carnatine

• Now she is 4 years , with normal development

Case 2

• Abdullah 2 years old male• Diagnosed by neonatal screening

As 3 MCC defeciency• Started on leucine free formula• L-carnatine• Did well , but at the age of

6 months mother started to givehim regular food , because he wasrefusing the formula

• Patient now at the age of 2 years withnormal development, no attacks of decompansation

3-Methylcrotonyl-CoA carboxylasedeficiency (3MCC deficiency

• -MethylCrotonyl-CoA Carboxylase (3-MCC) Deficiency has been recognized since 1984. It is a defect in the degradation of the amino acid leucine

CLINICAL PRESENTATION

• Varies --severe –mild• Onset—usually during first year ,later onset, even asymptomatic adult

• 1-catabolic• vomiting, lethargy, apnea, hypotonia, seizures, profound

hypoglycemia, metabolic acidosis, hyperammonemia,.

2-failure to thrive• beginning in the neonatal period or developmental delay

• Asymptomatic • women with 3-MCC deficiency may pass along the 3-MCC metabolite

transplacentally to their infants, who are then found to have elevated 3-MCC by newborn screening with tandem mass spectrometry, but who themselves do not have the disease

diagnosis

• tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine

• organic acid analysis finds elevation of 3-hydroxyisovaleric acid and usually 3-methylcrotonylglycin

• enzyme activity should be assayed in fibroblasts or leukocyte

• 3-MCC activity can also be measured in chorionic villusspecimens

• Mothers of all infants found to have elevated 3-MCC with newborn screening should be tested with a blood acylcarnitine profile to determine whether they have 3-MCC deficiency rather than their infant.

Hope for future