Leukodystrophies

Young child, Neurodegenerative dis with macrocephaly: canavan, Alexander, magelencephalic leukoencephalopathy with subcortical cyst.

Other leukoencephalopathy and macrocephaly: Childhood ataxia with central nervous system hypomylination(CACH)_Megalencephaly, L2 ---Glutaric aciduria, GM2 gangliosidosis

specific clinical features:
.Addison's disease in Adrenoleukodystrophy

hypodontia in Pol-III related or 4H leukodystrophy

Ectodermal Dysplasia

group of closely related conditions, of 150 different syndromes
"affecting the development or function of the teeth, hair, nails and sweat glands"

C/f
Absence of sweat glands: decreased or absent sweating
Poorly tolerate high grade fever, due to absence of sweating...high grade fever can lead to brain damage and seizures early.

Hypodontia or Adontia
Thin sparse depigmented hair
Decreased tear formation
Hypoplastic nail
Large forehead and depressed nasal bridge
May have, hearing and vision problem and learning disabilities
Recurrent nasal blockage can cause recurrent resp. Infections.

Diagnosis:
X ray bone teeth
Biopsy, skin & teeth
Genetic testing

Treatment:
According to symptoms
Avoid hot weather
Frequent bathing in cold water
Saline nasal spray, wig, denture, artificial tear

Prognosis:
Good, doesn't shorten life, take care of high temp.

Prevention:
Genetic testing

GENETICS: more than 7000 people affected worldwide, some disorders are restricted to a family

Sjögren-Larsson syndrome

Syndromic obesity

Cause: Alright syndrome
              Prader-Willi synd
               Bardel beidel synd(ciliopathy)
              Cohen syndrome

 

Aneuploidy

TURNER SYNDROME

urner synd: in foetus, presents with cystic hygroma, webbed neck, puffiness of hand and feet

TRISOMY 18

ABNORMALITIES Seen  IN more than 50% cases:

General.
Feeble cry, lethargic
 premature,or postmature;
polyhydramnios,
IUGR;
deficient skeletal muscle, subcutaneous and adipose tissue;
mental retardation.
Craniofacial.
Prominent occiput,
 narrow bifrontal diameter;
low-set, malformed auricles;
short palpebral fissures; small oral opening,
Narrow palatal arch;
Micrognathia.

Hands and Feet.
Clenched hand, tendency for overlapping of index finger over third, fifth finger over fourth;
 absence of distal crease on fifth finger with or without distal creases on third and fourth fingers;
 low-arch dermal ridge pattern on six or more fingertips;
 hypoplasia of nails, especially on fifth finger and toes;
short hallux, frequently dorsiflexed.

Thorax.
Short sternum, with reduced number of ossification centers; small nipples.

Abdominal Wall.
Inguinal or umbilical hernia and/or diastasis recti.

Pelvis and Hips.
Small pelvis, limited hip abduction.
Genitalia.
Male: cryptorchidism.

Skin. Redundancy, mild hirsutism of forehead and back, prominent cutis marmorata.
Cardiac. Ventricular septal defect, auricular septal defect, patent ductus arteriosus.

Eye syndrome

WAGR syndrome : autosomal dominant,
C/f: willms tumour with aniridia
Genetics: region on short arm of chr 11.
                  PAX6, WT1 genes

Cone rod dystrophy::
30 genes identified out of them 20 are AR.
ABC4 is most commonly involved.

Early infantile epileptic encephalopathy

also known as Otahara syndrome
onset: within the first 3 months of age.
description: tonic spasm, episodes lasting for 10 sec, may occur many times per day.
EEG: spasm coincides with the burst of high amplitude spikes and polyspikes.

may progress to
West syndrome: hypsarrhythmia, infantile spam, developmental delay
Dravet syndrome

7 genes, known

Gene imprinting

Examples:
Prader-Willi and Angelmansyndromes
and Beckwith-Wiedemann and
Russell-Silver syndromes

Hyperammonia

Sample should be sent in ice arterial blood preffered

Genetic testing registry

,

Pompe synd

Hypotonia with cardiomyopathy

Absent stomach bubbles

Causes: esophageal atresia, TOF, micrognathia causing obstruction, neuromuscular disorders causing reduced peristalsis
,

Inborn Error Of Metabolism

Factors wich precipitate acute illness in IEM
1. Diet:
Cane sugar : hereditary fructose deficiency
Milk: Galactosemia
Protein: Urea Cycle disorders, aminoacidopathy
Carbohydrates: pyruvate dehydrogenase and respiratory chain disorders

2. Infection, fasting and fever: Fatty acid Oxidation defects, few amino acid defects and organic aciduria.

3.Anaesthesia CD56e: in Homocystinuria

4. Drugs: porphyria and G6 Pd deficiency

Porphyria: group of disorder related to haem synthesis, involves dysfunction of enzyme necessary for haen synthesis

Two types, erythrocyte type(85%of haen synthesis occur in erythrocyte) and hepatic type(remaining 15%)

. 

If blood gases show an anion gap and metabolic acidosis , with hyperammonia...think of organic acid uria

Tyrosinaemia: succinylacetone to be done, alkaline phosphatase is high. Hepatosplenomegaly present

+Low iq , hyperactivity and autistic behaviour...D/d is phenylketonuria

+In fanconi anaemia, along with renal involvement check for signs of vitamin D resistant tickets

+ Oligosaccharidosis have similar phenotype as of mps that is coarse face, ham, bone dysplasia etc 

For screening , urine oligosaccharidosis are done,( this test has been done in few center only)

 Oligosacch..  are ab sent in few oligosaccharidosis like  

beta-mannosidosis, mucolipidosis II, and mucolipidosis III, 

May be detected in, Pompe disease (a glycogen storage disease), as well as Gaucher and Sandhoff diseases (sphingolipidoses). 

Fatty Acid Oxidation defect:

long-chain fatty acids (C16–C20) : mimics mitochondrial defects, presents as severe neonatal lactic acidosis, cardiomyopathy and hepatopathy.

CDG

Cerebellar atrophy is hallmark of CDG

+Child looking like MPS, but with normal urine screen

Disease   - enzyme def

GM 1 gangliosidisis - beta d galactosidase

+ Gaucher dis - GBA gene, 4 common mutation

L444P

N370S

84GG

IVS2+1

+ Odour --disease

Animal like.....PKU

Maple syrup.....MSUD

Cabbage like.....tyrocinemia 1, methionine malabsorption

Rotten fish..... Trimethylamine uria, dimethyl glycine uria

SKELETAL DYSPLASIA

ACHONDROPLASIA
S
Large C/f: disproportionate dwarfism: proximal limbs are shorter(Rhizomelic)
Short toe and fingers which is K/a Trident hand
Frontal bossing and large hand
Flat nasal bridge and midface hypoplasia
Spinal kypohosis or lordosis
Recurrent ear infection due to blockage of ETube
Varus/ valgus knee deformity

Genetics: AD, affected individual s are all heterozygous since homozygosity is lethal to foetus.
Mutation in fGFR 3 gene


PSEUDOACHONDROPLASIA:

features are similar to achondroplasia except macrocephaly and facial dysmorphism
form of spinoepiphyseal dysplasia
4 character: bowing of legs: genu valgum
                    laxity of all joints except elbow which has contracture
                    small irregular epiphysis, irregular broad metaphysis of long bones.
                 



SKELETAL DYSPLASIA WITH HEARING IMPAIRMENT:
1. diastrophic dysplasia
2. spondyloepiphyseal dysplasia congenita
3. morquio syndrome


+ Spondyloepiphyseal dysplasia seen in stickler syndrome

Overgrown newborn

Macrosomic newborn causes:
SOTOS syndrome

.Simpson gulabi behal syndrome..X linked

Malan synd
Marshall-smith synonyms

Weaver syndrome

Tattvon brown Rahman syndrome

Banyan Riley Ruvacaba syndrome

Cantu syndrome

Elejalde syndrome

Perelman syndrome

Beckwith weidemen syndrome:  ear crease on post part are specific,  patients may have placental mesenchymal tumour...Other feature..omphalocele, macroglossia

Inheritance

AUTOSOMAL DOMINANT

EXAMPLES:

1. Myotonic dystrophy type 1
2. Myotonic dystrophy type2
3. Achondroplasia

AUTOSOMAL RECESSIVE

1. Zellwegar syndrome

X LINKED DOMINANT

EXAMPLE:

1. X-linked hypophosphatemia
2. X-linked form of Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy
3. Incontinentia pigmenti
4. Rett syndrome and
5. Periventricular nodular heterotopia.

FSHD- fascialscapulohumoral disease,