With advent of disposable diapers, noticing dark-stained cloth diapers after washing no longer helps make the diagnosis… Most of the time, parents/patients never notice black urine… Degenerative surfaces and narrowing of joint space on x-ray… Historically, this syndrome is very important because it is the first biochemical disease described by Garrod… He is the man who invented biochemical genetics, termed the words “inborn errors of metabolism,” and came up with the idea that we’re all biochemically different… Interestingly, the diagnosis has been made in Egyptian mummies with black cartilage. KH, JW

Acral pain and paresthesias are very specific findings… You virtually never see them except in mercury/heavy metal poisoning… Pain is so severe that patients develop very peculiar behavior to help deal with it… Such as dunking their hands and feet in cold toilet water… The kid is often labeled “nuts” by parents and medical community… Low-dose dilantin works very well for the pain… Preliminary studies seem to show a reduction in the accumulation of glycosphingolipids… Interestingly, some transplanted patients show improvement in their pain… Group B blood groups tend to do worse… Of all X-linked recessive diseases, this one has the largest number of symptomatic female carriers… Enzyme replacement therapy is now available. KH, JW

Infantile and adult forms may share mutation… Type II’s are kids with big spleens and livers who neurologically deteriorate rapidly… There’s essentially no residual enzyme in the infants… Type I’s always have some residual enzyme… The brain probably doesn’t need as much enzyme to dispose of the lipid… We are screening Ashkenazi Jews before pregnancy for both enzyme and DNA… Now we can treat symptomatic patients with enzyme… Livers and spleens shrink right up with the enzyme… There’s a joke that we have to provide the kids with suspenders along with their Ceredase because their pants start falling down… The enzyme can’t help the neuropathic forms (types II and III) because it doesn’t cross the blood-brain barrier… Bony problems improve with enzyme if one intervenes early on… All kids who present with hepatosplenomegaly are initially worked up with an enzyme assay. KH, JW

The gene has been cloned and most mutations in Ashkenazi Jews are pretty well known… We screen Ashkenazi Jewish couples preconceptually for carrier status… Same gene for types A and B, different mutations… Type B’s have higher residual enzyme and thus don’t get neurologic sequelae… B’s can get terrible lung disease… We have an ongoing study looking at replacement therapy in type B… Type C is a different gene seen in French-Canadians… The defect in C secondarily affects sphingomyelin… As in all babies with vomiting, their formulae are changed five times prior to diagnosis… Cherry red spots are also seen in Tay-Sachs, generalized sialidosis, and Sandhoff’s disease. KH, JW

The coarse facies may not be apparent when they’re very young… The early tip off to the pediatrician is hepatosplenomegaly and a gibbous deformity of the lower spine… Early on, get a lateral lumbar spine and/or lateral skull seeing the j-shaped deformity of the sella turcica… Kids with Sanfilippo’s are physically very mild, but mentally can be difficult with hyperactivity, aggressive behavior… Four or five different enzyme defects can lead to Sanfilippo’s… As opposed to Hurler’s where different mutations in the same gene gives different disease… Most kids with storage disease seem to begin life reaching their early milestones and then drop off… If the mother tells you the kid isn’t doing what he’s supposed to be doing at 6 months or so, you really need to start looking… To obtain skin for fibroblast cultures, I (KH) take a tuberculin syringe, raise a bleb in the skin with lidocaine, and then come out the other end of the bleb… I lift it and shear off the base with a scalpel… Fibroblasts grow beautifully… We do echoes and spine films on all of them… As with Down’s, patients with Hurler’s and Morquio’s lack their occipito-atlantic prominence that anchors the cervical spine to the skull… They can split and become quadriplegic… You must fuse this area… We keep them in physical therapy to prevent contractures… The group in Minnesota has studied bone marrow transplants in all patients with mucopolysaccharidoses (MPS)… They believe it may mitigate the retardation… They’ve transplanted a kid with Hurler’s in utero… They may be slowing things down some but those cells are not going to correct the brain… You’re going to have to wait for gene therapy… Corneal transplants stay clear because they produce their own enzyme… The MPS society is very active… Gene replacement is being done on animal models like the Siamese cat for Maroteaux-Lamy’s. KH, JW

Clearly, we look for it in a kid who is acidotic in a precomatose state… We also look for all the other inborn errors that can do this… Any child who presents with failure to thrive and skin manifestations should to have their urine screened for organic acids. KH, JW

We don’t see it anymore… We’re screening them all at birth… I (KH) remember seeing a kid with phenylketonuria (PKU) who came from blonde-haired parents… He looked like an albino… Pregnant women with PKU must be on strict diet control to protect heterozygote fetus from malformations and severe retardation… Patients need to be on formula diet for rest of their lives… Tastes terrible… If the patient’s not under control, the mousy odor will be present… The enzyme is not expressed in cultured amniocytes… Prenatal diagnosis by molecular techniques if the mutation is known… People are using polymerase chain reaction (PCR) in situations where fibroblast or lymphocyte cultures don’t express enough enzyme to make the diagnosis. KH, JW