High Yield Genes

Presenilin 1

Autosomal Dominant mutation on Chromosome 14

Involves the cleavage of Amyloid Precursor protein (APP) --> mutation leads to increased production of amyloid peptides

*** Most common cause of inherited early onset Alzheimer's Dementia

Others:

- Presenilin 2 on Chromosome 1 (early onset AD)

- APP gene on chromosome 21 (early onset AD, increase risk in Down's)

APOE4 vs E2

E4 = 5-15x risk higher risk for dev late onset AD & CAA

E2 = lower risk

MAPT gene

Autosomal dominant mutation on chromosome 17 a/w FTDP-17

FTDP-17 is Parkinsonism w/ early bheav/personality changes and cognitive problems.

Genes associated with PD

LRRK2 (autosomal dominant) - 10% familial, 5% sporadic

PARK1/2 - mutation in alpha synuclein

GBA gene - assoc with gaucher disease and higher risk for PD

C9ORF72

Hexanucleotide repeat a/w familial FTD/ALS

PGRN

Autosomal Dominant mutation in progranulin which is a/w increased risk for FTD

CACNA1S

hypokalemic periodic paralysis

CACNA1A

Voltage gated calcium channel on chromosome 19

multiple phenotypes:

-sporadic and familial hemiplegic migraine

-episodic ataxia type 2 (ataxia and vertigo lasting hours, triggered by physical exertion or emotional stress, and the presence of nystagmus between episodes. The condition typically presents in childhood or young adulthood and responds well to acetazolamide)

-SCA type 6

PRRT2

1. Paroxysmal Kinesiogenic Dyskinesia (PKD) [short attacks, <1 min, many times per day, triggered by sudden voluntary movements, treated with sodium blocking ASMs like CMZ/PHT/OXC]

2. Hemiplegic migraines

3. Benign familial infantile seizures

ATP1A2/A3

Familial hemiplegic migraine / Alternating hemiplegia of childhood

KCNA1

episodic ataxia type 1 (Very brief episodes lasting seconds usually. Also associated with Epilepsy, Myokymia excess startle in between episodes)

DMPK

myotonic dystrophy, CTG repeats on chromsome 19

(Myotonic dystrophy protein kinase involved in muscle cell regulation

Or central hypersomnia

FLH1

X-linked recessive mutation leading to Emery Dreifuss Muscular Dystrophy (other common is LMNA -laminopathy)

Clinical sx:

- Childhood onset humeroperoneal weakness and wasting

- early contractures of elbow flexors and ankle flexors

- cardiac disease

RYR1

(Calcium channelopathy)

Central core myopathy (neonatal hypotonia + weakness)

Malignant Hyperthermia

Exertional Rhabdo

FMRI

X-lined dominant mutation involving Trinucleotide repeat CGG a/w Fragile X

Merlin

mutation in NF-2

FKTN

(alpha-dystroglycanopathies)

Altered expression of Fukutin a/w Fukuyama congenital muscular dystrophy

Main Symptoms

Muscle Issues: Low muscle tone (hypotonia), weak muscles, and tight joints (contractures).

Brain Issues: Delayed development, learning challenges, and seizures.

Eye Problems: Vision impairment or structural eye defects.

Management and Care

Supportive Treatment: Physical therapy and stretching help keep joints flexible.

Mobility Aids: Braces and wheelchairs help patients move around.

Respiratory Care: Breathing support and prompt treatment for lung infections are vital.

Consultation: A specialized care team manages heart, feeding, and seizure needs. [1]

PMP22

Autosomal Dominant duplication on chromosome 17 leading to CMT 1A. The extra gene makes too much protein, which harms the myelin sheath that helps nerve signals travel.

Autosomal Dominant Deletion on chromosome 17 leading to HNPP. Losing one copy of this gene means nerves have fragile insulation that is easily damaged by mild pressure, stretching, or everyday use

ELN

Elastin - affected in chromosomal anomaly 7q11.23 aka Williams syndrome (elfin facies, ID, hypersocial)

Trisomy 13

Patau syndrome: microcephaly, cleft palate, ID, hypotonia, holoprosencephaly

HHT

Aut dom mutation leading to Hereditary Hemorrhagic Telengiectasia aka Osler-Weber-Rendu

Other genes: ACVRL1, ENG, SMAD4

Symptoms

Frequent nosebleeds: Often start in childhood and happen regularly.

Telangiectasias: Small red or purple spider veins or spots on the lips, tongue, face, and fingertips.

Anemia: Low red blood cell counts caused by chronic blood loss from the nose or digestive tract.

Digestive bleeding: Bleeding in the stomach or intestines that can result in dark stools

ATM

Autosomal recessive mutation leading to Ataxia Telengiectasia Syndrome

Key Signs and Symptoms

Ataxia: Poor balance and muscle coordination, usually appearing as an unsteady walk when a toddler begins to move.

Telangiectasias: Tiny, dilated spider-like blood vessels that appear in the whites of the eyes and on sun-exposed areas of the skin.

Immune Deficiencies: Low antibody levels leading to frequent sinus and lung infections.

Other Neurological Issues: Slurred speech, involuntary jerky movements, and trouble moving the eyes side-to-side

HTT

Autosomal Dominant mutation leading to Huntington disease (CAG repeats)

DYT1

Encodes Torsin A leading childhood dystonia

ABCA1

Tanger Disease

Enlarged orange tonsils, peripheral neuropathy, hepatosplenomegalh

GCH1

Autosominal dominant mutation leading to Dopa responsive dystonia (usually age 6-10)

ATP7A/7B

7A - Menkes

7B - Wilson

SLC2A1

GLUT-1 deficiency

Infantile/neonatal seizures, dev delay, spasticity, ataxia

Treat with ketogenic deit

RFC1

pentanucleotide repeat AAGGG causing CANVAS syndrome

Cerebellar ataxia, Neuropathy, Vestibular, Arflexia Syndrome (preceded by chronic dry cough)

CHRNA4

Aut Dom mutation in AChR subunits leading Nocturnal Familial Frontal Lobe Epilepsy

Also mutations in CHRNA2/B4

SCN4A

Aut Dom Sodium channelopathy leading Paramyotonia Congenita (worse in cold and activity) and Hyperkalemic Periodic Paralysis (freq episodeslasting minutes to hours, triggered by rest after exercise, fasting/skipped meals)

CLCN1

Chloride channelopathy leading to Myotonia Congenita (worse after rest and improves with activity)

LGI-1

Autosomal Dominant Partial Epilepsy with Auditory Features (APEAF) - localized to lateral temp lobe

DMD

X-linked recessive mutation in dystrophin production leading to Duchenne/Becker MD

AR

X-linked recessive mutation with CAG trinucelotide repeats in the Androgen Gene leads to Spinal-and-bulbar muscular atrophy (SBMA or Kennedy's disease)

5p del

cri du chat - miceocephaly, cat like cry, high pitched, DD/ID

Prader Willi syndrome

15q11.2-q13 paternal deletion (or imprinting)

Angelman syndrome

15q11.2-q13 maternal deletion (or imprinting)

SLC6A19 gene

Autosomal recessive mutation leading to Hartnup disease

Loss of tryptophan absorption causing episodic ataxia/confusion, photosensitive rash, neutral aminoaciduria

CCM/KRIT1

Autosomal Dominant mutation leading to familial cavernous malformations

KIAA1840 gene

SPG11 related hereditary spastic paraplegia (autosomal recessive) - progressive spastic paraparesis, congition, thin CC, "ears of the lynx" periventricular T2 hyperintensities

Frataxin

Autosomal Rec mutation involving GAA trinucleotide repeats leading Frederick ataxia.

GLA

Fabry disease

Inheritance: X-linked

Enzyme def: alpha-galactosidase-A

Accumulation: Globotriasylceramide

Findings: Hypohydrosis, angiokeratomas, renal failure, small fiber painful neuropathy, strokes, cataracts

GBA

Gaucher disease

Inheritance: autosomal recessive

Enzyme def: Glucocerebrosidase

Accumulation: Glucocerebroside

Findings: Osteoporosis, femoral head necrosis, ataxia, hepatosplenomegaly. Gaucer cells (lipid laden cells with tissue paper cytoplasm)

GLRA1

The glycine receptor is the main inhibitory neurotransmitter receptor in the brainstem and spinal cord, and its dysfunction leads to pathologically enhanced startle disease called hyperkplexia

GALC mutation

Krabbe disease

Autosomal recessive mutation in beta-galactocerebrosidase leading to accumulation of galactocebroside and psychosine.

Findings: Globoid cells (large macrophages with abundant cytoplasm), optic atrophy, leukodystrophy, ataxia, irritability, peripheral neuropathy

GAA gene

Pompe disease

Autosomal recessive mutation leading to deficiency in alpha-glucosidase leading to accumulation of cerebroside sulfate

cardiomyopathy, hepatomegaly, profressive muscle weakness, macroglossia, hypotonia. biopsy with PAS-positive vascuolar myopathic changes

Tret with recomibant human GAA gene therapy