Table 3.
Menkes Disease Symptoms.
| Birth and Neonatal Period | Enzyme Deficiency | Comments |
|---|---|---|
| Preterm | AOC (histaminase) | One-third before 37 weeks |
| Premature rupture of fetal membranes | LOX | |
| Weight | - | One-third less than 2500 g |
| Length | - | |
| Head circumference | - | |
| Apgar score | - | Quick test at 1 and 5 min, in rare cases, also 10 min after birth |
| Denver scale | - | Developmental score for milestones in young children according to age |
| Bayley score | - | Cognitive, language, and motor developmental infants and toddlers score |
| Hydrops fetalis | LOX | Severe swelling (oedema) |
| Intrauterine growth retardation | LOX, SUMF1 | Small for gestational age |
| Decreased fetal movements | - | |
| Neonatal onset | - | Rarely recognized before hair changes at 2–3 month |
| Neonatal death | - | |
| Early death | - | Usually before three years |
| Failure to thrive | - | |
| Feeding difficulties | DBH, LOX | Poor sucking and swallowing |
| Floppy infant | COX, LOX | |
| Poor head control | COX | |
| Dysautonomy | DBH | |
| Infantile spasms | COX | Shivers or a small jerks in series |
| Irritability | DBH, PAM, SUMF1 | |
| Babinski reflex | DBH, PAM, SUMF1 | Upward movement of the big toe sign of pyramidal dysfunction |
| Anxiety | DBH, PAM, SUMF1 | |
| Increased response to noise | DBH, PAM, SUMF1 | |
| Lethargy | DBH, PAM, SUMF1 | Decreased alertness |
| Respiratory distress | LOX, SOD3 | |
| Icterus/jaundice | CP, LOX | Photo therapy resistant |
| External features | ||
| - Head and neck | ||
| Face lacking in expression | DBH | Low mimic |
| Pallor | TYR | Light skin color |
| Hypertelorism | LOX, SUMF1 | Widely spaced eyes |
| Nystagmus | DBH, LOX, TYR | Difficulty in controlling eye movements |
| Blepharophimosis | LOX | Narrowing of eye opening |
| Photophobia | AOC, TYR | Light intolerance |
| Keratitis | AOC, LOX | Cornea inflammation |
| Conjunctivitis | AOC, LOX | Eye inflammation |
| Ptosis | DBH, LOX | Droopy eyelids |
| Miosis | DBH | Excessive constriction of pupils |
| High arched (cupid) eyebrows | LOX, SUMF1 | |
| Ophthalmoplegia | DBH, LOX | |
| Cherubic appearance | LOX, SUMF1 | |
| Microcephaly | LOX, SUMF1 | <2 SD for age |
| Brachycephaly | LOX, SUMF1 | |
| Frontal bossing | LOX, SUMF1 | |
| Occipital bossing | LOX, SUMF1 | |
| Long philtrum | LOX, SUMF1 | |
| High forehead | LOX, SUMF1 | |
| High-arched palate | LOX, SUMF1 | |
| Small chin | LOX, SUMF1 | |
| Pudgy cheeks | SUMF1 | |
| Flat central face | LOX, SUMF1 | |
| Depressed nasal bridge | LOX, SUMF1 | |
| Nasal congestion | LOX | |
| Hypoplastic mandibles | LOX, SUMF1 | |
| Micrognathia | LOX, SUMF1 | |
| Retrognathia | LOX, SUMF1 | |
| Drooping jaws | SUMF1 | |
| Low set ears | LOX, SUMF1 | |
| Large ears | LOX, SUMF1 | |
| Occipital exostoses | LOX | Calcified exostoses palpable from occiput, uncommon |
| Internal jugular phlebectasia | LOX | |
| - Chest | ||
| Pectus excavatum | LOX | |
| Pectus carinatum | LOX | |
| Neurological symptoms | ||
| Corpus callosum agenesis | SUMF1 | Absence of brain structure that connects the two hemispheres |
| Dysautonomia | DBH | |
| Cerebellar hypoplasia | LOX | |
| Mental retardation | COX, PAM, SOD1 | |
| Motor retardation | COX, PAM, SOD1 | |
| Loss of milestones | - | Progressive neurologic defects |
| Hypothermia | DBH, PAM | Subnormal body temperature |
| Hypoglycemia | DBH, PAM | Subnormal sugar values |
| Nasal congestion | DBH | |
| West syndrome | COX | Epileptic encephalopathy |
| Seizures | COX | Refractory and early onset |
| Clonic seizures | COX | |
| Myoclonic seizures | COX | |
| Tonic seizures | COX | |
| Motor dysfunction | DBH | |
| Ataxia | DBH, PAM, SOD1, SUMF1 | |
| Spasticity | COX | |
| Hypertonia | DBH | |
| Hypotonia | DBH | |
| Eye symptoms | ||
| Cataract | LOX | |
| Myopia | LOX | |
| Nystagmus | DBH, LOX, TYR | Difficulty in controlling eye movements |
| Strabismus | TYR | |
| Blepharophimosis | LOX | Narrowing of eye opening |
| Photophobia | AOC, TYR | Light intolerance |
| Keratitis | AOC, LOX | Cornea inflammation |
| Conjunctivitis | AOC, LOX | |
| Ptosis | DBH, LOX | Droopy eyelids |
| Miosis | DBH | Excessive constriction of pupils |
| Reduced visual acuity | TYR | |
| Optic discs palor | TYR | |
| Optic atrophy | TYR | Abnormal electroretinogram (ERG) |
| Visual loss | TYR | Visual evoked potential (VIP) |
| Retinal and iris depigmentation | TYR | |
| Iris trans-luminescence | TYR | |
| Iris microcysts | SUMF1, TYR | |
| Hypopigmented fundus | TYR | Fundoscopy |
| Ear symptoms | ||
| Hearing loss | LOX, PAM, TYR | Brain stem auditory evoked potential (BAEP) |
| Hair and skin symptoms | ||
| Fine, silvery and brittle hair | AOC, TYR, SUMF1 | Short, stubby, friable |
| Depigmented scalp hair | TYR, SUMF1 | Lusterless, silvery, steel wool |
| Sparse hair | AOC, SUMF1 | Rubbing against pillow may feel like unshaven stubbles |
| Alopecia | AOC, SUMF1 | Lack of hair |
| Fetal hair may be unaffected | - | Soft |
| Pili torti | SUMF1 | Hair twisted about their own axis |
| Trichorhexis nodosa | SUMF1 | Frying and splitting of hair ends |
| Monilethrix | SUMF1 | Varying diameters of the shafts |
| Cupid eyebrows | LOX, SUMF1 | Eyebrows with a high arch |
| Sparse eyebrows | AOC, SUMF1 | Look like old man’s eyebrows |
| Sparse eyelashes | AOC, SUMF1 | Breaks easily |
| Seborrhea | AOC, SUMF1 | Dry and scaly skin |
| Erythroderma | AOC, SUMF1 | Generalized exfoliative dermatitis with redness and scaling |
| Cutis laxa | HEPHL1, LOX | Lax and wrinkled skin may give a progeria like appearance |
| Pale skin | PAM, TYR | Almost like an albino |
| Anhydrosis | DBH, LOX | Inability to sweat normally |
| Doughy skin | LOX | Swelling of subcutaneous tissue |
| Lymphedema | LOX | Swelling due to poor lymphatic system |
| Dentation | ||
| Hyperplastic gums | LOX | Prominent gums |
| Dental abnormalities | LOX | |
| Enamel defects | LOX | |
| Delayed eruption | LOX | |
| Biconically shaped incisors | LOX | |
| Lung symptoms | ||
| Acute respiratory distress syndrome | AOC, LOX, SOD3, SUMF1 | |
| Chronic obstructive pulmonary disease | AOC, LOX, SOD3, SUMF1 | |
| Emphysema | LOX, SOD3, SUMF1 | Damaged air sacs (alveoli) with breathing difficulty |
| Cardiovascular symptoms | ||
| Congenital heart disease | COX, LOX | About 5% |
| Angiopathy | AOC, APP, LOX, SOD3 | Disease of arteries, veins, and capillaries |
| Tortuous blood vessels | LOX | Twisted with frayed and split inner walls |
| Bleeding tendency | FV+VIII, LOX | |
| Mild coagulation deficiency | FV+VIII | |
| Hematomas | LOX | |
| Subdural hematomas | LOX | |
| Intracranial hemorrhage | LOX | |
| Cephalohematomas | LOX | Prevalent at birth |
| Gastrointestinal symptoms | ||
| Chronic diarrhea | AOC | |
| Vomiting | AOC | |
| Bowel dysfunction | AOC | |
| Gastrointestinal polyps | LOX | |
| Hiatal hernia | LOX | |
| Hepatic symptoms | ||
| Hepatomegaly | COX, SOD1, SUMF1 | Low hepatic copper gives low enzymatic activity |
| Icterus | CP, ATP7B | Yellowish color of skin and eyes |
| Steatosis | COX, SOD1 | Fatty liver |
| Genitourinary symptoms | ||
| Bladder diverticula | LOX | |
| Bladder rupture | LOX | |
| Ureteral obstruction | LOX | |
| Glomerulonephritis | LOX | |
| Urinary tract infection | LOX | |
| Vesico-ureteral reflux | LOX | |
| Hydronephrosis | LOX | Partial urinary tract blockage |
| Diaphragmatic hernia | LOX | |
| Umbilical hernias | LOX | |
| Inguinal hernia | LOX | |
| Cryptorchidism | LOX, SUMF1 | Undescended t esticles |
| Connective tissue symptoms | ||
| Loose/hypermobile joints | LOX | |
| Tortuous vessels | LOX | |
| Wrinkled and loose/extensible skin | LOX | |
| Soft skin / edema | LOX | |
| Musculoskeletal symptoms | ||
| - Skeletal—neck and chest | ||
| Cervical spine anomalies | LOX | Mimics non-accidental lesions |
| Short, broad clavicles | LOX | |
| Flaring of the ribs | LOX | |
| Short, broad ribs | LOX | |
| Pectus excavatum | LOX | Sunken breastbone |
| Pectus carinatum | LOX | Protruding breastbone; “pigeon chest” |
| - Skeletal—limbs | ||
| Congenital bone fractures | LOX | Symmetrical uncommon in “battered child”/NAI |
| Long-bone fractures | LOX | |
| Metaphyseal spurring | LOX | Can resemble scurvy |
| Diaphyseal periosteal reaction | LOX | |
| Cortical thickening | LOX | |
| Short humeri | LOX | |
| - Skeletal—others | ||
| Wormian bones | LOX | Intrasutural supernumerary bones, not found in child abuse |
| Spondylolysis | LOX, SUMF1 | Fractures of vertebra |
| Osteroporosis | LOX, SUMF1 | Brittle bones |
| Osteopenia | LOX, SUMF1 | |
| Cartilage malformation | LOX, SUMF1 | |
| Joint laxity | LOX | |
| Limb dislocations | LOX | |
| Metaphyseal widening | LOX | |
| Osteochondrodysplasia | LOX, SUMF1 | |
| Occipital horn exostoses | LOX | Uncommon in MNK, but can be observed from 2 years |
| - Muscles | ||
| Motor neuron disease | SOD1, LOX | |
| Investigations | Activity measured | |
| MR MRI and MRA | Neuroimaging | Magnetic Resonance and computerized tomography; cerebral atrophy, cortical areas of low density, diffuse cerebral and cerebellar volume loss, white-matter, and basal ganglia changes |
| CT | Neuroimaging | |
| EEG | Brain activity | Hypsarrhythmia, diffuse, multifocal spike activity |
| Radiography | Bone | Symmetrical metaphyseal flaring and spurring of ribs, and cervical fractures may mimic non-accidental trauma, but these are not symmetrical; skull wormian bones are not seen in child abuse |
| Arteriography | Vasculature | Elongated and tortuous cerebral and systemic vessels |
| Ultrasonography | Bladder, bowel | Diverticulae and polyps |
| Light Microscopy | Hair examination | Pili torti, trichorexis nodosa, monilethrix |
| Echocardiography | Heart | Heart murmur |
| ERG | Electroretinogram | Optic atrophy |
| VIP | Visual evoked potential | Loss of vision; retinal and macular degeneration |
| Fundoscopy | Eye background, macula | Hypopigmented |
| BAEP | Brain stem auditory evoked potential | Hearing loss |
| Cell culture | Radioactive copper test | Increased accumulation and retention |
| Tissue copper | ICPMS; AA | Increased in CVS, placenta, muscle; liver low |
| Biomarkers | ||
| Boy | ATP7A | X-linked |
| Family history of male infant death | ATP7A | X-linked |
| Hyperbilirubinemia | ATP7B | Transient, but prolonged and light therapy resistant |
| Low plasma copper | ATP7A | Diagnostic from 4–6 weeks |
| Low free Cu | ATP7A | Diagnostic from birth |
| Low ceruloplasmin | CP | Diagnostic from 4–6 weeks |
| High RBC (Red Blood Cells) Cu | SOD1 | Erythrocyte SOD1 in neonates |
| Anemia | HEPH, CP | May be hypochrome |
| Neutropenia | LOX | Decreased neutrophils |
| Thromboembolism | FV+VIII | Blood clot breaking loose and plugs other vessels |
| Urinary Cu low to normal | ATP7A | MT |
| Low liver Cu | ATP7A | Diagnostic from birth |
| High placenta Cu | ATP7A | Diagnostic from birth; CVS diagnostic prenatally |
| High metallothionein levels | ATP7A | MT1 and MT2 (diagnostic?) |
| Plasma DA/NE ratio increased | DBH | Diagnostic from birth |
| Urinary HVA/VMA ratio increased | DBH | Diagnostic from birth |
| Hypoglycemia | SUMF1, PAM, DBH | Transient |
| High blood lactate | COX | CSF, intermittent |
| Pyruvate | COX | Intermittent |
| Hyperammoniemia | COX | Intermittent |
| High plasma glutamic acid | COX | Intermittent, alpha-ketogluterate conversion |
| Respiratory chain deficiencies | COX | Indicative |
| Intracellular Cu accumulation | ATP7A | Diagnostic, tissue culture |
| Molecular screening of ATP7A | ATP7A | Definitive diagnosis |
| Pathology | ||
| Purkinje cell pathologies | SOD1 | Faulty arborization and “weeping willow” |
| Ragged red fibers | COX | Subsarcolemmal aggregates of mitochondria in muscle fiber |
| Alder Reilly anomaly | SUMF1 | Vacuolization of blood cells; observed in GAG deficiencies |
| Metachromasia | SUMF1 | Color staining change of accumulated tissue sugar sulfatides |
| Pili torti | SUMF1 | Hair twisted about their own axis |
| Trichorhexis nodosa | SUMF1 | Frying and splitting of hair ends |
| Monilethrix | SUMF1 | Varying diameters of the shafts |
| Differential diagnosis: | ||
| NAI | LOX | Non-accidental injuries; >10% symmetric changes think MNK |
| Osteogenesis imperfecta | LOX | Brittle bones and bone dysplasias |
| Mitochondrial disorder | COX | Compromised energy production affecting all organs and tissues |
| Organic acid uria | COX | Defective mitochondrial matrix metabolism |
| Cutis laxa | LOX | Loose and wrinkled skin in an infant |
| Progeria | LOX, SUMF1 | Old age syndrome in young people |
| Syndromes with hair abnormalities | SUMF1, AOC | |
| Glutamine defects | COX | Defective mitochondrial matrix metabolism |
| MSD | SUMF1 | Multiple sulfatase deficiency |
| MPS | SUMF1 | Mucopolysaccaridoses |
| MLP | SUMF1 | Mucolipidoses |
| Leukodystrophy | SUMF1 | E.g., metachromatic leukodystrophy |
| DBH deficiency, congenital | DBH | CNS Cu deficiency |